Probiotics For People With Hepatic Encephalopathy (Review) : Cochrane

Cochrane Database of Systematic Reviews
Probiotics for people with hepatic encephalopathy (Review)
Dalal R, McGee RG, Riordan SM, Webster AC
Dalal R, McGee RG, Riordan SM, Webster AC.

Probiotics for people with hepatic encephalopathy.
Cochrane Database of Systematic Reviews 2017, Issue 2. Art. No.: CD008716.
DOI: 10.1002/14651858.CD008716.pub3.
www.cochranelibrary.com

Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . . 4
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
ADDITIONAL SUMMARY OF FINDINGS . . . . . . . . . . . . . . . . . . . . . . . . . . 18
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
Analysis 1.1. Comparison 1 Probiotic versus placebo or no intervention, Outcome 1 All-cause mortality. . . . . . 92
Analysis 1.2. Comparison 1 Probiotic versus placebo or no intervention, Outcome 2 No recovery (incomplete resolution of
clinical symptoms). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
Analysis 1.3. Comparison 1 Probiotic versus placebo or no intervention, Outcome 3 Adverse events. . . . . . . 94
Analysis 1.4. Comparison 1 Probiotic versus placebo or no intervention, Outcome 4 Quality of life. . . . . . . 96
Analysis 1.5. Comparison 1 Probiotic versus placebo or no intervention, Outcome 5 Plasma ammonia concentration (final
and change scores) (µmol/L). . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
Analysis 2.1. Comparison 2 Probiotic versus lactulose, Outcome 1 All-cause mortality. . . . . . . . . . . . 98
Analysis 2.2. Comparison 2 Probiotic versus lactulose, Outcome 2 No recovery (incomplete resolution of clinical
symptoms). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99
Analysis 2.3. Comparison 2 Probiotic versus lactulose, Outcome 3 Adverse events. . . . . . . . . . . . . 100
Analysis 2.4. Comparison 2 Probiotic versus lactulose, Outcome 4 Health-related quality of life. . . . . . . . 102
Analysis 2.5. Comparison 2 Probiotic versus lactulose, Outcome 5 Plasma ammonia concentration (final and change scores)
(µmol/L). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . . 109
INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
Probiotics for people with hepatic encephalopathy (Review) i

[Intervention Review]
Probiotics for people with hepatic encephalopathy
Rohan Dalal1 , Richard G McGee2 , Stephen M Riordan3 , Angela C Webster4
1
Sydney Medical School, Westmead Hospital, Sydney, Australia. 2 Institute of Endocrinology and Diabetes, The Children’s Hospital
at Westmead, Westmead, Australia. 3 Gastrointestinal and Liver Unit, The Prince of Wales, Randwick, Australia. 4 Sydney School of
Public Health, The University of Sydney, Sydney, Australia
Contact address: Richard G McGee, Institute of Endocrinology and Diabetes, The Children’s Hospital at Westmead, Locked Bag 4001,
Westmead, NSW, 2145, Australia. dr.richardmcgee@gmail.com.
Editorial group: Cochrane Hepato-Biliary Group.

Publication status and date: New search for studies and content updated (conclusions changed), published in Issue 2, 2017.
Citation: Dalal R, McGee RG, Riordan SM, Webster AC. Probiotics for people with hepatic encephalopathy. Cochrane Database of
Systematic Reviews 2017, Issue 2. Art. No.: CD008716. DOI: 10.1002/14651858.CD008716.pub3.
ABSTRACT
Background
Hepatic encephalopathy is a disorder of brain function as a result of liver failure or portosystemic shunt or both. Both hepatic
encephalopathy (clinically overt) and minimal hepatic encephalopathy (not clinically overt) significantly impair patient’s quality of life
and daily functioning, and represent a significant burden on healthcare resources. Probiotics are live micro-organisms, which when
administered in adequate amounts, may confer a health benefit on the host.
Objectives
To determine the beneficial and harmful effects of probiotics in any dosage, compared with placebo or no intervention, or with any other
treatment for people with any grade of acute or chronic hepatic encephalopathy. This review did not consider the primary prophylaxis
of hepatic encephalopathy.
Search methods
We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, Science Citation
Index Expanded, conference proceedings, reference lists of included trials, and the World Health Organization International Clinical
Trials Registry Platform until June 2016.
Selection criteria
We included randomised clinical trials that compared probiotics in any dosage with placebo or no intervention, or with any other
treatment in people with hepatic encephalopathy.
Data collection and analysis
We used standard methodological procedures expected by The Cochrane Collaboration. We conducted random-effects model meta-
analysis due to obvious heterogeneity of participants and interventions. We defined a P value of 0.05 or less as significant. We expressed
dichotomous outcomes as risk ratio (RR) and continuous outcomes as mean difference (MD) with 95% confidence intervals (CI).
Probiotics for people with hepatic encephalopathy (Review) 1
Main results
We included 21 trials with 1420 participants, of these, 14 were new trials. Fourteen trials compared a probiotic with placebo or no
treatment, and seven trials compared a probiotic with lactulose. The trials used a variety of probiotics; the most commonly used group
of probiotic was VSL#3, a proprietary name for a group of eight probiotics. Duration of administration ranged from 10 days to 180
days. Eight trials declared their funding source, of which six were independently funded and two were industry funded. The remaining
13 trials did not disclose their funding source. We classified 19 of the 21 trials at high risk of bias.
We found no effect on all-cause mortality when probiotics were compared with placebo or no treatment (7 trials; 404 participants; RR
0.58, 95% CI 0.23 to 1.44; low-quality evidence). No-recovery (as measured by incomplete resolution of symptoms) was lower for
participants treated with probiotic (10 trials; 574 participants; RR 0.67, 95% CI 0.56 to 0.79; moderate-quality evidence). Adverse
events were lower for participants treated with probiotic than with no intervention when considering the development of overt hepatic
encephalopathy (10 trials; 585 participants; RR 0.29, 95% CI 0.16 to 0.51; low-quality evidence), but effects on hospitalisation and
change of/or withdrawal from treatment were uncertain (hospitalisation: 3 trials, 163 participants; RR 0.67, 95% CI 0.11 to 4.00; very
low-quality evidence; change of/or withdrawal from treatment: 9 trials, 551 participants; RR 0.70, 95% CI 0.46 to 1.07; very low-
quality evidence). Probiotics may slightly improve quality of life compared with no intervention (3 trials; 115 participants; results not
meta-analysed; low-quality evidence). Plasma ammonia concentration was lower for participants treated with probiotic (10 trials; 705
participants; MD -8.29 µmol/L, 95% CI -13.17 to -3.41; low-quality evidence). There were no reports of septicaemia attributable to
probiotic in any trial.
When probiotics were compared with lactulose, the effects on all-cause mortality were uncertain (2 trials; 200 participants; RR 5.00,
95% CI 0.25 to 102.00; very low-quality evidence); lack of recovery (7 trials; 430 participants; RR 1.01, 95% CI 0.85 to 1.21; very
low-quality evidence); adverse events considering the development of overt hepatic encephalopathy (6 trials; 420 participants; RR
1.17, 95% CI 0.63 to 2.17; very low-quality evidence); hospitalisation (1 trial; 80 participants; RR 0.33, 95% CI 0.04 to 3.07; very
low-quality evidence); intolerance leading to discontinuation (3 trials; 220 participants; RR 0.35, 95% CI 0.08 to 1.43; very low-
quality evidence); change of/or withdrawal from treatment (7 trials; 490 participants; RR 1.27, 95% CI 0.88 to 1.82; very low-quality
evidence); quality of life (results not meta-analysed; 1 trial; 69 participants); and plasma ammonia concentration overall (6 trials; 325
participants; MD -2.93 µmol/L, 95% CI -9.36 to 3.50; very low-quality evidence). There were no reports of septicaemia attributable
to probiotic in any trial.
Authors’ conclusions
The majority of included trials suffered from a high risk of systematic error (‘bias’) and a high risk of random error (‘play of chance’).
Accordingly, we consider the evidence to be of low quality. Compared with placebo or no intervention, probiotics probably improve
recovery and may lead to improvements in the development of overt hepatic encephalopathy, quality of life, and plasma ammonia
concentrations, but probiotics may lead to little or no difference in mortality. Whether probiotics are better than lactulose for hepatic
encephalopathy is uncertain because the quality of the available evidence is very low. High-quality randomised clinical trials with
standardised outcome collection and data reporting are needed to further clarify the true efficacy of probiotics.
PLAIN LANGUAGE SUMMARY

Probiotics for people with hepatic encephalopathy
Why the review is important
Hepatic encephalopathy is a disorder of brain function as a result of liver failure or portosystemic shunt or both. Both hepatic
encephalopathy (clinically overt) and minimal hepatic encephalopathy (not clinically overt) significantly impair patient’s quality of
life and daily functioning and represent a significant burden on healthcare resources. Probiotics are live micro-organisms, which when
administered in adequate amounts may confer a health benefit on the host. We searched and summarised randomised trials about the
benefits and harms of any probiotic in any dosage, compared with placebo or no intervention, or with any other treatment for people
with any grade of acute or chronic hepatic encephalopathy.
Main findings
The evidence is current to June 2016. Of the 21 included trials including 1420 participants, 14 trials compared a probiotic with placebo
or no treatment and seven trials compared a probiotic with lactulose. The treatment duration of the trials ranged from 10 days to 180
days.
Compared with placebo or no intervention, probiotics probably improve recovery and may lead to improvements in the development
of overt hepatic encephalopathy, quality of life, and plasma ammonia concentrations, but may lead to little or no difference in mortality.
Probiotics may slightly improve quality of life when compared with no intervention; however, this conclusion is based on three trials
with low-quality evidence. Whether probiotics are better than lactulose for hepatic encephalopathy is uncertain because the quality of
the available evidence was very low. There were no reports of septicaemia attributable to probiotic in any trial. There was no evidence
of more adverse events with probiotics when compared to placebo or lactulose.
Funding
Eight trials declared their funding source, of which six were independently funded and two were industry funded. The remaining 13
trials did not disclose their funding source.
Limitations of the review
Many of the included trials suffered from a high risk of systematic error (‘bias’) and a high risk of random error (‘play of chance’).
Accordingly, we consider the evidence to be of low quality.
Conclusions
Compared with placebo or no intervention, probiotics probably improve recovery and may lead to improvements in the development
of overt hepatic encephalopathy, quality of life, and plasma ammonia concentrations, but probiotics may lead to little or no difference
in mortality. Whether probiotics are better than lactulose for hepatic encephalopathy is uncertain because the quality of the available
evidence was very low. High-quality randomised clinical trials with standardised outcome collection and data reporting are needed to
further clarify the true efficacy of probiotics.

Probiotics for people with hepatic encephalopathy (Review) S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]
Probiotic versus placebo or no intervention for people with hepatic encephalopathy
Patient or population: people with hepatic encephalopathy

Setting: inpatients
Intervention: probiotic
Comparison: placebo/ no intervention
Outcomes Anticipated absolute effects* (95% CI) Relative effect No of participants Quality of the evidence Comments
(95% CI) (studies) (GRADE)
Risk with placebo/ no Risk with probiotic

intervention
All-cause m ortality Study population RR 0.58 404 ⊕⊕

(f ollow-up: 2 weeks to 3 (0.23 to 1.44) (7 RCTs) LOW 1,2
m onths) 51 per 1000 30 per 1000
(12 to 73)
M oderate
25 per 1000 14 per 1000

(6 to 36)
No-recovery (incom - Study population RR 0.67 574 ⊕⊕⊕

plete resolution of clin- (0.56 to 0.79) (10 RCTs) M ODERATE 2
ical sym ptom s) 790 per 1000 529 per 1000
(f ollow-up: 1 m onth to (442 to 624)
3 m onths)
M oderate
877 per 1000 588 per 1000

(491 to 693)
4
Adverse events - Overt Study population RR 0.29 585 ⊕⊕

hepatic encephalopa- (0.16 to 0.51) (10 RCTs) LOW 1,2
thy 168 per 1000 49 per 1000
(f ollow-up: 2 weeks to 3 (27 to 86)
m onths)
M oderate
169 per 1000 49 per 1000

(27 to 86)
Adverse Study population RR 0.70 551 ⊕

events - Change of / or (0.46 to 1.07) (9 RCTs) VERY LOW 1,2,3
withdrawal f rom treat- 204 per 1000 143 per 1000
m ent (94 to 219)
(f ollow-up: 1 m onth to
3 m onths) M oderate
158 per 1000 111 per 1000

(73 to 169)
Quality of lif e - - - 115 ⊕⊕

(f ollow-up: 1 m onth to (3 RCTs) LOW 1,2
3 m onths)
Plasm a am m onia con- - The m ean plasm a - 705 ⊕⊕

centration (f inal and am m onia concentra- (10 RCTs) LOW 2,3
change scores) (µm ol/ tion (f inal and change
L) scores) (µm ol/ L) in the
(f ollow-up: 1 m onth to intervention group was
6 m onths) 8.29 f ewer (13.17 f ewer
to 3.41 f ewer)
* The risk in the intervention group (and its 95% conf idence interval) is based on the assum ed risk in the com parison group and the relative effect of the intervention (and its
95% CI).
CI: conf idence interval; RCT: random ised clinical trial; RR: risk ratio
5
GRADE Working Group grades of evidence

High quality: We are very conf ident that the true ef f ect lies close to that of the estim ate of the ef f ect.
M oderate quality: We are m oderately conf ident in the ef f ect estim ate: The true ef f ect is likely to be close to the estim ate of the ef f ect, but there is a possibility that it is
substantially dif f erent.
Low quality: Our conf idence in the ef f ect estim ate is lim ited: The true ef f ect m ay be substantially dif f erent f rom the estim ate of the ef f ect.
Very low quality: We have very little conf idence in the ef f ect estim ate: The true ef f ect is likely to be substantially dif f erent f rom the estim ate of ef f ect
1
Downgraded one level f or serious concerns or two levels f or very serious concerns of im precision (based on f ew events and
wide conf idence intervals).
2 Downgraded one level f or serious concerns or two levels f or very serious concerns of trials judged as at high risk of bias
(m ost studies at high risk of bias).

3 Downgraded one level f or serious concerns or two levels f or very serious concerns of inconsistency of the outcom es in
ef f ects.
6
BACKGROUND in addition to the osmotic effect of lactulose, which encourages
removal of toxic metabolic products such as ammonia, it is also
known to have a bifidogenic effect (De Preter 2006; Bass 2010).
Description of the condition Amongst other potential reasons, one rationale behind the use of
probiotics for hepatic encephalopathy is to reduce the prevalence
Hepatic encephalopathy (also known as portosystemic en-
of harmful ammonia-producing bacteria in the gastrointestinal
cephalopathy) is a reversible neuropsychiatric disorder seen in the
system. Probiotics are thought to reduce blood ammonia levels by
context of either acute or chronic liver failure or portosystemic
several mechanisms including decreasing bacterial urease activity,
shunting, or both (Ferenci 2002). Hepatic encephalopathy is char-
decreasing ammonia absorption by decreasing pH, decreasing in-
acterised by complex cognitive dysfunction, which is indepen-
testinal permeability, and improving nutritional status of gut ep-
dent of sleep dysfunction or problems with overall intelligence
ithelium (Poh 2012).
(Blei 2001). Minimal hepatic encephalopathy is a milder form of
the same condition, which does not have obvious clinical signs
(Stewart 2007; Bajaj 2011). The onset of hepatic encephalopa-
thy indicates a poor prognostic outcome. It may also reduce Why it is important to do this review
quality of life and level of daily functioning (Groeneweg 1998; Hepatic encephalopathy significantly impairs patient’s quality of
Arguedas 2003). The pathophysiology of hepatic encephalopa- life and daily functioning, job performance, and overall mortal-
thy is still uncertain, but the prevailing assumption is that dif- ity (Groeneweg 1998; Arguedas 2003; Stinton 2013). Caring for
ferent toxins, such as false neurotransmitters, natural benzodi- and treating patients with hepatic encephalopathy is a significant
azepines, short-chain fatty acids, and mercaptans enhance the neg- burden on the healthcare system. In 2005, hepatic encephalopa-
ative effects of ammonia on the level of consciousness (Butterworth thy cost the US healthcare system an estimated USD 4676.7
1987; Blei 2001; Vaquero 2003). Current therapeutic options million, increasing to USD 7244.7 million in 2009 (Stepanova
include intensive supportive care, identification and correction 2012). Previous Cochrane Hepato-Biliary Group systematic re-
of the precipitating causes, tailored dietary restrictions, non-ab- views have only shown moderate, and in some cases no ben-
sorbable disaccharides, L-ornithine L-aspartate, and/or oral an- efit for current or proposed therapies for hepatic encephalopa-
tibiotics (Riordan 1997; Blei 2001; Als-Nielsen 2003; Als-Nielsen thy, which include non-absorbable disaccharides, oral antibiotics,
2004a; Als-Nielsen 2004b; Als-Nielsen 2004c; Jiang 2009). branched-chain amino acids, and dopamine (Als-Nielsen 2003;
Als-Nielsen 2004a; Als-Nielsen 2004b; Als-Nielsen 2004c; Junker
2014; Gluud 2015). Based on a preliminary analysis, it is esti-
Description of the intervention mated that the literature on probiotics in hepatic encephalopa-
Probiotics are live micro-organisms, which when administered thy has doubled since this systematic review was last published in
in adequate amounts may confer a health benefit on the host 2011, hence this update will improve the evidence base on the use
(Schrezenmeir 2001). However, the dose needed to confer a health of probiotics in hepatic encephalopathy.
benefit is unknown for many conditions. Probiotics commonly
come from two groups of bacteria, Lactobacillus or Bifidobacterium.
Within each group, there are different species (e.g. Lactobacillus
acidophilus and Bifidobacterium bifidus), and within each species, OBJECTIVES
different strains (or varieties). A few common probiotics, such as
To determine the beneficial and harmful effects of probiotics in
Saccharomyces boulardii, are yeasts, which are different from bac-
any dosage, compared with placebo or no intervention or with
teria. Therapeutic effects may be strain specific, and so caution
any other treatment for people with any grade of acute or chronic
must be exerted in generalising results from one species to another.
hepatic encephalopathy. This review did not consider the primary
While probiotics are generally considered safe, adverse events have
prophylaxis of hepatic encephalopathy.
been attributed to their use (Besselink 2008).
How the intervention might work METHODS

There is some evidence for an alteration in the composition of the
gastrointestinal bacterial flora of people with liver disease (Rolfe
2000). Modulation of the gut microbiota is an important aspect of Criteria for considering studies for this review
current therapy; the current conventional treatment option of the
broad-spectrum antibiotic rifaxamin is minimally absorbed and
Types of studies
targets gram-negative and gram-positive enteric bacteria. Similarly,

We included randomised trials that compared probiotics with symptoms). We considered an individual to be ’completely
placebo or no intervention, or with any other treatment for people resolved’ if he or she was not in a state of hepatic encephalopathy
with hepatic encephalopathy. We applied no restrictions on lan- based on the trial’s definition of hepatic encephalopathy used in
guage of publication, publication date, or publication status. We the inclusion process.
excluded quasi-randomised trials. 3. Adverse events: number and type of adverse events, defined
as participants with any untoward medical occurrence. We
summarised adverse events that led to treatment discontinuation
Types of participants
and those that did not lead to treatment discontinuation
separately. We defined serious adverse events according to the
Inclusion criteria International Conference on Harmonisation (ICH) guidelines
(ICH-GCP 1997), as any event that led to death, was life-
We included all people with any grade of acute or chronic hepatic
threatening, required inpatient hospitalisation or prolongation of
encephalopathy in connection with acute and chronic liver disease
existing hospitalisation, resulted in persistent or significant
as well as acute hepatic failure, no matter the aetiology of liver
disability, and any important medical event that may have
disease or factors precipitating the hepatic encephalopathy.
jeopardised the patient or required intervention to prevent it. We
considered all other adverse events as non-serious.
Exclusion criteria 4. Quality of life: as measured by the 36-Item Short Form
We excluded trials with participants in whom a diagnosis of hepatic Health Survey (SF-36) or other similar validated scales, such as
encephalopathy was not confirmed, that is where altered mental the Sickness Impact Profile (SIP) (Brazier 1992; Ware 1994).
status or cognitive function was not confirmed by a standardised
neuropsychological assessment. Where co-interventions such as Secondary outcomes
medication were being administered, they had to be administered
1. Change of or withdrawal from treatment: number of
equally across the relevant intervention groups of the trial so that
participants who changed/withdrew from their allocated
fair comparisons could be made.
treatment regimen.
2. Sepsis: number of participants with one or more episodes of
Types of interventions sepsis (confirmed by a positive blood culture).
Any probiotic at any dose for any duration. Additional co-inter- 3. Change in plasma ammonia concentration.
ventions were allowed if received by all trial intervention groups 4. Duration of stay in hospital: measured in days.
and deemed sufficiently similar across trial groups. Where synbi-
otics were used (a combination of a prebiotic and a probiotic; a
prebiotic is a substance that stimulates the growth of probiotics), Search methods for identification of studies
the control group must have received a similar prebiotic to be in-
cluded in the review, such that across trial groups the difference
in intervention(s) was probiotic alone. For example, where pro- Electronic searches
biotic and lactulose were compared to antibiotic plus lactulose,
For this update, we searched The Cochrane Hepato-Biliary Group
the comparison would have been probiotics versus antibiotic. If a
Controlled Trials Register (Gluud 2016), The Cochrane Central
trial compared probiotics and prebiotics versus prebiotics, the trial
Register of Controlled Trials (CENTRAL) in the Cochrane Li-
would have been considered a probiotic versus placebo trial, as
brary, MEDLINE Ovid, Embase Ovid, and Science Citation In-
the difference between the two groups would have been probiotic
dex Expanded (Web of Science) (Royle 2003) all on the 14th of
alone.
June 2016. The search strategies with the time spans of the searches
are given in Appendix 1. The search filter for randomised trials
Types of outcome measures in MEDLINE (OvidSP) was created by Lefebvre 2011, and the
We assessed all outcomes at time points reported by the au- search filter for randomised trials in Embase (OvidSP) was created
thors, but, where possible, also summarised at one, two, three, six by Sharon 2006.
months, and one year. We also searched the World Health Organization International
Clinical Trial Registry Platform (WHO ICTRP) (www.who.int/
ictrp) for ongoing and unpublished trials up to June 2016 us-
Primary outcomes ing an advanced search for the condition ’hepatic encephalopa-
1. All-cause mortality: number of participants dead. thy’ and intervention ’probiotic’, and using an advanced search
2. Number of participants who did not recover from hepatic for the condition ’hepatic encephalopathy’. As a quality check,
encephalopathy (defined as incomplete resolution of clinical we searched the ClinicalTrials.gov database (clinicaltrials.gov/ct2/

home) in September 2016, even though ClinicalTrials.gov is in- We entered data into Review Manager 5 software and checked the
cluded as one of the registers within the WHO ICTRP portal. data for accuracy (RevMan 2011).
Searching other resources Assessment of risk of bias in included studies

We handsearched the proceedings of three relevant conferences: We followed the instructions given in the Cochrane Handbook
1. American Association for the Study of Liver Disease for Systematic Reviews of Intervention (Higgins 2011) and the
(AASLD) from 2005 to 2014; Cochrane Hepato-Biliary Group Module (Gluud 2016). Method-
2. European Association for the Study of the Liver (EASL) ological quality was defined as the confidence that the design and
from 2005 to 2014; the report of the randomised clinical trial would restrict bias in
3. Digestive Diseases Week (DDW) from 2005 to 2014, using the comparison of the treatment groups (Moher 1998). Accord-
the keywords ’hepatic encephalopathy’, ’probiotic’, ing to empirical evidence (Schulz 1995; Moher 1998; Kjaergard
’bifidobacterium’, ’lactobacillus’, and ’liver disease’. 2001; Wood 2008; Lundh 2012; Savovi 2012; Savovi 2012a),
We identified further trials through reference lists of relevant we assessed the risk of bias of the trials using the following ’Risk
articles and by contacting content experts and authors of in- of bias’ domains.
cluded trials. We applied no date or language restrictions. We
translated non-English language articles using Google Translate Sequence generation
(translate.google.com.au/). Mandarin translations were provided • Low risk of bias: the method used was either adequate (e.g.
by Sunny Wu. computer-generated random numbers, table of random
numbers) or unlikely to introduce bias.
• Unclear risk of bias: there was insufficient information to
Data collection and analysis assess whether the method used was likely to introduce
confounding.
• High risk of bias: the method used was not best practise for
Selection of studies randomisation.
Working independently, three review authors conducted trial se-
lection and data extraction. None of the review authors was
Allocation concealment
blinded to journal or author names. Disagreements were resolved
by consensus. • Low risk of bias: the method used (e.g. central allocation)
was unlikely to induce bias on the final observed effect.
Data extraction and management assess whether the method used was likely to induce bias on the
We extracted the following information using a standardised data estimate of effect.
extraction form. • High risk of bias: the method used (e.g. open random
• General information: author(s), title, source, contact allocation schedule) was likely to induce bias on the final
address, year of trial, country of trial, language of publication, observed effect.
year of publication.
• Trial characteristics: design (randomised clinical trial), Blinding of participants
randomisation method, manner of recruitment, sampling
• Low risk of bias: blinding was performed adequately, or the
method, duration of intervention period, length of follow-up,
outcome was not likely to be influenced by lack of blinding.
reason for and number of dropouts and withdrawals, adverse
events.
assess whether the type of blinding used was likely to induce bias
• Participants: baseline characteristics of participants in
on the effect.
treatment groups such as sex, age, prevalence of comorbidities
• High risk of bias: no blinding or incomplete blinding, and
(e.g. diabetes), inclusion and exclusion trial criteria.
the outcome was likely to be influenced by lack of blinding.
• Trial setting: e.g. inpatient/outpatient department,
emergency department.
• Detailed description of both the intervention and the Blinding of personnel
comparison intervention, type, dose, and duration of • Low risk of bias: blinding was performed adequately, or the
probiotic(s). outcome was not likely to be influenced by lack of blinding.
• Outcomes: specific outcome reported, assessment • Unclear risk of bias: there was insufficient information to
instrument used, scoring range where appropriate. assess whether the type of blinding used was likely to induce bias
• Any co-interventions. on the effect.

• High risk of bias: no blinding or incomplete blinding, and considered trials judged as being at unclear risk of bias or high risk
the outcome was likely to be influenced by lack of blinding. of bias in one or more of the specified individual domains as trials
at high risk of bias. We contacted authors of the original reports
to provide further details when any of the above information was
Blinding of outcome assessors
unclear.
• Low risk of bias: blinding was performed adequately, or the
outcome measurement was not likely to be influenced by lack of
blinding. Measures of treatment effect
• Unclear risk of bias: there was insufficient information to We conducted data analysis according to the guidelines presented
assess whether the type of blinding used was likely to induce bias in the Cochrane Handbook for Systematic Reviews of Interventions
on the estimate of effect. (Higgins 2011) and the Cochrane Hepato-Biliary Group Module
• High risk of bias: no blinding or incomplete blinding, and (Gluud 2016).
the outcome measurement was likely to be influenced by lack of For dichotomous data, we presented results as summary risk ratio
blinding. (RR) with 95% confidence intervals (CI). For continuous data,
we presented results as mean difference (MD) if outcomes were
measured in the same way amongst trials.
Incomplete outcome data
• Low risk of bias: the underlying reasons for missing data
were unlikely to cause treatment effects to depart from plausible Dealing with missing data
values, or appropriate methods were employed to handle missing Data for all participants were analysed in the group to which they
data. are allocated, regardless of whether or not they received the allo-
• Unclear risk of bias: there was insufficient information to cated intervention. If in the original reports participants were not
assess whether the missing-data mechanism in combination with analysed in the group to which they were randomised and there
the method used to handle missing data was likely to induce bias was sufficient information in the trial report, we attempted to re-
on the estimate of effect. store these participants to the correct group, that is we conducted
• High risk of bias: the crude estimate of effects (e.g. intention-to-treat analysis where it was possible to do so. Where
complete-case estimate) was clearly biased due to the underlying data were missing, we sought clarification from the authors of the
reasons for missing data, and the methods used to handle trial. If intention-to-treat analysis was not possible, we conducted
missing data were unsatisfactory. available-case analysis or per-protocol analysis.
Selective outcome reporting Assessment of heterogeneity

• Low risk of bias: the trial protocol was available, or the We assessed heterogeneity amongst trials, when appropriate, using
study author provided further information about prespecified the I² and Cochran Q statistics. Where we detected substantial
outcomes and all of the trial’s prespecified outcomes that were of heterogeneity (I² more than 50% or P less than 0.10), we explored
interest in the review were reported or similar. this heterogeneity by prespecified subgroup analysis and sensitivity
• Unclear risk of bias: there was insufficient information to analysis.
assess whether the magnitude and direction of the observed
effect were related to selective outcome reporting. Assessment of reporting biases
• High risk of bias: not all of the trial’s prespecified primary
Where we suspected reporting bias, we attempted to contact trial
outcomes were reported or similar.
authors to provide the missing outcome data. When missing data
were thought to potentially introduce serious bias, the impact
Other bias of including such trials in the overall assessment of results was
• Low risk of bias: the trial was independently funded, e.g. by explored by a sensitivity analysis. Where there were at least 10
a government organisation or university. trials, we also used funnel plot asymmetry to assess the existence
• Unclear risk of bias: the trial did not declare its funding of bias.
source.
• High risk of bias: the trial was industry funded, e.g. by a Data synthesis
pharmaceutical company, or an author was an employee of a
We conducted statistical analysis with random-effects model meta-
pharmaceutical company.
analyses using Review Manager 5 software (RevMan 2011). We
We considered trials judged as being at low risk of bias in all of used random-effects models for all analyses where trials examined
the specified individual domains as trials at low risk of bias. We the same intervention and the trials populations and methods were

judged to be sufficiently similar. We originally planned to also con- risk of bias (methodological quality), inconsistency, imprecision,
duct fixed-effect model meta-analysis, but abstained due to obvi- indirectness, and publication bias (GRADEpro).
ous heterogeneity of participants and intervention. We defined a We defined the levels of evidence as ’high’, ’moderate’, ’low’, or
P value of 0.05 or less as significant. ’very low’:
• High certainty: this research provides a very good
indication of the likely effect; the likelihood that the effect will
Subgroup analysis and investigation of heterogeneity
be substantially different is low.
The following were priori subgroup analyses. • Moderate certainty: this research provides a good indication
• Type of probiotic (by genus): Lactobacillus, Bifidobacteria, of the likely effect; the likelihood that the effect will be
mixed, or unclear. substantially different is moderate.
• Grade of hepatic encephalopathy: minimal compared to • Low certainty: this research provides some indication of the
overt. likely effect; however, the likelihood that the effect will be
• Duration of therapy. substantially different is high.
• MELD (Model for End-Stage Liver Disease) score. • Very low certainty: this research does not provide a reliable
• Co-interventions used. indication of the likely effect; the likelihood that the effect will
• Trials with low risk of bias compared to trials with high risk be substantially different is very high.
of bias.
We assessed differences among subgroups by test of interaction
(Altman 1996).
RESULTS
Sensitivity analysis
We carried out sensitivity analysis when we detected significant
heterogeneity (I² more than 50% or P less than 0.10) to determine
Description of studies
the source, that we sequentially removed trials from the analysis See: Characteristics of included studies; Characteristics of excluded
to determine which trial or trials were contributing to the hetero- studies; Characteristics of ongoing studies.
geneity.
Results of the search
’Summary of findings’ tables The process of identifying reports of randomised clinical trials
We used the GRADE system to evaluate the quality of the evidence for inclusion in the original review and in the review update is
for outcomes reported in the review, considering the within-study outlined in Figure 1.

Figure 1. Study flow diagram.

The original review published in 2011 included a total of seven
trials reported in nine publications. Of the 21 included trials, 14 trials compared a probiotic with
In this update, the electronic searches of the Cochrane Hepato-Bil- placebo or no treatment in 785 participants (Liu 2004; Bajaj 2008;
iary Group Controlled Trials Register (n = 13), the Cochrane Cen- Nair 2008; Malaguarnera 2010; Qiao 2010; Pereg 2011; Saji 2011;
tral Register of Controlled Trials (CENTRAL) (n = 58), MED- Dhiman 2013a; Zhitai 2013; Bajaj 2014a; Lunia 2014; Sharma
LINE (n = 85), Embase (n = 272), and Science Citation Index 2014; Shavakhi 2014; Vlachogiannakos 2014). Three trials com-
Expanded (n = 291) identified a total of 719 publications. We pared a probiotic with lactulose in 200 participants (Loguercio
identified six additional trials from reference list (n = 4) and trials 1987; Loguercio 1995; Mouli 2014). Four trials compared a pro-
registry (n = 3) searching. biotic both with placebo and with lactulose in 435 participants
After excluding 188 duplicates and 197 records overlapping with (Sharma 2008; Mittal 2009; Zhao 2013; Ziada 2013).
the original search, 341 unique records remained. Of these, we The probiotics used in each trial are in Table 1.
excluded 302 after reviewing titles and abstracts, and of the re- Seventeen trials enrolled participants with minimal hepatic en-
maining 39 records, which we assessed after reviewing their full cephalopathy (Liu 2004; Bajaj 2008; Nair 2008; Sharma 2008;
texts, we excluded a further 15 records. Three of the 39 records Mittal 2009; Qiao 2010; Pereg 2011; Saji 2011; Dhiman 2013a;
were identified as ongoing trials (ACTRN12610001021066; Zhao 2013; Ziada 2013; Bajaj 2014a; Lunia 2014; Mouli 2014;
IRCT201211012417N9; NCT01798329); therefore, the results Sharma 2014; Shavakhi 2014; Vlachogiannakos 2014), and three
were not available for use in the review; information about these tri- trials enrolled participants with overt hepatic encephalopathy
als is provided in Characteristics of studies awaiting classification. (grade I or II according to the West Haven criteria) (Loguercio
Consequently, the review update contributed an additional 14 new 1987; Loguercio 1995; Malaguarnera 2010). The type of hep-
trials reported in 20 publications. atic encephalopathy in one trial was unclear from the text (Zhitai
Seventeen reports were of 13 new trials (Loguercio 1995; Qiao 2013).
2010; Saji 2011; Dhiman 2013a; Zhao 2013; Zhitai 2013; Ziada
2013; Bajaj 2014a; Lunia 2014; Mouli 2014; Sharma 2014;
Excluded studies
Shavakhi 2014; Vlachogiannakos 2014). Three reports were of
one previously excluded trial now included after we obtained the We excluded a total of 320 newly identified and separate publica-
manuscript from the author (Nair 2008). tions in the update. One previously excluded study was included
A total of 30 reports (publications and abstracts) of 21 trials qual- after a manuscript containing further information was obtained
ified for inclusion in the review (Figure 1). from the author (Nair 2008).
Four of these 21 trials were available as an abstract across four
different reports (Dhiman 2013a; Zhitai 2013; Lunia 2014; Risk of bias in included studies
Vlachogiannakos 2014), whilst 17 of these 21 trials were published
Reporting of trial methodology was incomplete for the majority of
in 26 different reports.
the domains, as summarised in Figure 2 and Figure 3. We classified
most trials at a high risk of bias (with the exception of Bajaj 2014a
Included studies and Nair 2008).

Figure 2. Figure 2. Risk of bias graph: review authors’ judgements about each risk of bias item presented as
percentages across all included trials.

Figure 3. Figure 3. Risk of bias summary: review authors’ judgements about each risk of bias item for each
included trial.

Allocation
17 trials were unclear (Loguercio 1987; Loguercio 1995; Liu
Sequence generation was adequately performed in 12 trials 2004; Nair 2008; Mittal 2009; Malaguarnera 2010; Qiao 2010;
(Loguercio 1995; Bajaj 2008; Nair 2008; Sharma 2008; Mittal Pereg 2011; Dhiman 2013a; Zhao 2013; Zhitai 2013; Ziada
2009; Malaguarnera 2010; Saji 2011; Zhao 2013; Bajaj 2014a; 2013; Bajaj 2014a; Lunia 2014; Sharma 2014; Shavakhi 2014;
Mouli 2014; Sharma 2014; Shavakhi 2014), inadequately per- Vlachogiannakos 2014).
formed in one trial (Liu 2004), and unclear in eight trials
(Loguercio 1987; Qiao 2010; Pereg 2011; Dhiman 2013a; Zhitai
2013; Ziada 2013; Lunia 2014; Vlachogiannakos 2014). Other potential sources of bias
Seven trials reported adequate allocation concealment (Loguercio Eight trials declared their funding source (Loguercio 1987; Bajaj
1995; Liu 2004; Nair 2008; Mittal 2009; Bajaj 2014a; Mouli 2008; Nair 2008; Pereg 2011; Bajaj 2014a; Mouli 2014; Sharma
2014; Sharma 2014), two trials reported inadequate allocation 2014; Shavakhi 2014), of which six were independently funded
concealment (Bajaj 2008; Sharma 2008), and 12 trials were un- (Bajaj 2008; Nair 2008; Bajaj 2014a; Mouli 2014; Sharma 2014;
clear about their method of allocation concealment (Loguercio Shavakhi 2014), and two were industry funded (Loguercio 1987;
1987; Malaguarnera 2010; Qiao 2010; Pereg 2011; Saji 2011; Pereg 2011). The remaining trials did not disclose their funding
Dhiman 2013a; Zhao 2013; Zhitai 2013; Ziada 2013; Lunia source (Loguercio 1995; Liu 2004; Sharma 2008; Mittal 2009;
2014; Shavakhi 2014; Vlachogiannakos 2014). Malaguarnera 2010; Qiao 2010; Saji 2011; Dhiman 2013a; Zhao
2013; Zhitai 2013; Ziada 2013; Lunia 2014; Vlachogiannakos
2014).
Blinding
Three trials reported adequate blinding of participants, out- Effects of interventions
come assessors, and personnel (Loguercio 1987; Nair 2008; Bajaj
2014a). One trial reported adequate blinding of outcome assessors See: Summary of findings for the main comparison Probiotic
and participants, but was unclear regarding blinding of personnel for people with hepatic encephalopathy; Summary of findings 2
(Saji 2011). Three trials reported adequate blinding of outcome Probiotics for people with hepatic encephalopathy
assessors, but reported no blinding of participants and personnel Probiotic versus placebo or no treatment
(Bajaj 2008; Ziada 2013; Mouli 2014). One trial was unclear re- Primary outcomes
garding blinding of outcome assessors, but reported no blinding All-cause mortality
of participants and personnel (Shavakhi 2014). One trial reported There were no significant differences in all-cause mortality (
blinding of participants, but was unclear regarding blinding of Analysis 1.1; 7 trials; 404 participants; RR 0.58, 95% CI 0.23 to
personnel and outcome assessors (Vlachogiannakos 2014). Three 1.44; low quality of evidence).
trials did not blind participants, personnel, or outcome assessors Number of participants who did not recover from hepatic en-
(Sharma 2008; Mittal 2009; Sharma 2014). The remaining nine cephalopathy
trials were unclear regarding the conduct of blinding (Loguercio No-recovery (as measured by incomplete resolution of symptoms)
1995; Liu 2004; Malaguarnera 2010; Qiao 2010; Pereg 2011; was significantly lower for participants treated with probiotic than
Dhiman 2013a; Zhao 2013; Zhitai 2013; Lunia 2014). with placebo or no intervention overall (Analysis 1.2; 10 trials;
574 participants; RR 0.67, 95% CI 0.56 to 0.79; moderate quality
of evidence), at one month (Analysis 1.2 (Analysis 1.2.1); 4 trials;
Incomplete outcome data 228 participants; RR 0.75, 95% CI 0.58 to 0.96), and at three
Incomplete outcome data were adequately addressed in six trials months (Analysis 1.2 (Analysis 1.2.3); 3 trials; 229 participants;
(Bajaj 2008; Nair 2008; Saji 2011; Ziada 2013; Bajaj 2014a; RR 0.58, 95% CI 0.43 to 0.78), but not at two months (Analysis
Shavakhi 2014), inadequately addressed in four trials (Loguercio 1.2 (Analysis 1.2.2); 3 trials; 117 participants; RR 0.65, 95% CI
1987; Loguercio 1995; Sharma 2008; Pereg 2011), and unclear in 0.38 to 1.10).
the remaining trials (Liu 2004; Mittal 2009; Malaguarnera 2010; Adverse events
Qiao 2010; Dhiman 2013a; Zhao 2013; Zhitai 2013; Lunia 2014; Adverse events were lower for participants treated with probiotic
Mouli 2014; Sharma 2014; Vlachogiannakos 2014). than with placebo or no intervention when considering the de-
velopment of overt hepatic encephalopathy (Analysis 1.3 (Analy-
sis 1.3.1); 10 trials; 585 participants; RR 0.29, 95% CI 0.16 to
Selective reporting 0.51; low quality of evidence), but there were no significant dif-
Four trials were free of selective outcome reporting (Bajaj 2008; ferences for hospitalisation (Analysis 1.3 (Analysis 1.3.3); 3 trials;
Sharma 2008; Saji 2011; Mouli 2014), while the remaining 163 participants; RR 0.67, 95% CI 0.11 to 4.00; very low quality

of evidence) or change of/or withdrawal from treatment (Analysis of therapy, test for subgroup differences: Chi² = 1.68, df = 2 (P =
1.3 (Analysis 1.3.5); 9 trials; 551 participants; RR 0.70, 95% CI 0.43); co-interventions used, test for subgroup differences: Chi² =
0.46 to 1.07; very low quality of evidence). 3.57, df = 2 (P = 0.17) (Table 2).
Quality of life Plasma ammonia
There were no significant differences in quality of life scores for We detected no significant differences for the following subgroup
participants treated with probiotic than with no intervention in the analyses: type of probiotic used, test for subgroup differences: Chi²
SF-36 Physical Functioning Scale (Analysis 1.4 (Analysis 1.4.1); 1 = 3.26, df = 3 (P = 0.35); grade of hepatic encephalopathy, test
trial; 20 participants; MD 0.00, 95% CI -5.47 to 5.47; low qual- for subgroup differences: Chi² = 0.03, df = 1 (P = 0.85); duration
ity of evidence) and the SF-36 Mental Health Scale (Analysis 1.4 of therapy, test for subgroup differences: Chi² = 1.09, df = 2 (P =
(Analysis 1.4.2); 1 trial; 20 participants; MD -4.00, 95% CI -9.82 0.58); co-interventions used, test for subgroup differences: Chi² =
to 1.82; low quality of evidence). There was no significant differ- 4.40, df = 2 (P = 0.11) (Table 2).
ence in quality of life score for participants treated with probiotic Quality of the evidence
than with no intervention in the Total Sickness Impact Profile In the analyses comparing probiotic versus placebo or no interven-
(SIP) Score (Analysis 1.4 (Analysis 1.4.3); 2 trials; 95 participants; tion (Summary of findings for the main comparison), we down-
MD -3.66, 95% CI -7.75 to 0.44; low quality of evidence), but graded the quality of the evidence to ’moderate’ for the outcome
there were significant differences for change in SIP Psychological no-recovery because the included trials were at high risk of bias.
Score (Analysis 1.4 (Analysis 1.4.4); 2 trials; 95 participants; MD Likewise, we downgraded the quality of the evidence for the out-
-3.54, 95% CI -4.95 to -2.12; low quality of evidence) and change comes adverse events -- overt hepatic encephalopathy and plasma
in SIP Physical Score (Analysis 1.4 (Analysis 1.4.5); 2 trials; 95 ammonia concentration to low because the included trials were at
participants; MD -2.94, 95% CI -4.44 to -1.44; low quality of high risk of bias and the results were inconsistent. We downgraded
evidence). A reduced SIP score indicates improved quality of life. the quality of the evidence for the outcomes all-cause mortality
Secondary outcomes and adverse events -- change of or withdrawal from treatment or
Sepsis both -- to very low because the included trials were at high risk of
There were no reports of septicaemia attributable to probiotic in bias and the results were inconsistent or imprecise, or both.
any trial. Heterogeneity
Change in plasma ammonia concentration Heterogeneity was demonstrated for the outcome no-recovery
Plasma ammonia concentration was significantly lower for par- (Analysis 1.2) (Chi² = 17.48, df = 9 (P = 0.04); I² = 48%) and did
ticipants treated with probiotic than with no intervention over- not seem attributable to type of probiotic used, grade of hepatic en-
all (Analysis 1.5; 10 trials; 705 participants; MD -8.29 µmol/L, cephalopathy, duration of therapy, or co-interventions used. Het-
95% CI -13.17 to -3.41; low quality of evidence), at one month erogeneity was demonstrated for the outcome plasma ammonia
(Analysis 1.5 (Analysis 1.5.1); 5 trials; 357 participants; MD -5.55 concentration (Analysis 1.5) (Chi² = 47.32, df = 9 (P < 0.00001);
µmol/L, 95% CI -10.67 to -0.42), at three months (Analysis 1.5 I² = 81%) and did not seem attributable to type of probiotic used,
(Analysis 1.5.3); 1 trial; 73 participants; MD -6.79 µmol/L, 95% grade of hepatic encephalopathy, duration of therapy, or co-inter-
CI -10.39 to -3.19), and at six months (Analysis 1.5 (Analysis ventions used (Table 2).
1.5.3); 1 trial; 64 participants; MD -31.08 µmol/L, 95% CI - Probiotic versus lactulose
40.50 to -21.66), but not at two months (Analysis 1.5 (Analysis Primary outcomes
1.5.2); 4 trials; 211 participants; MD -5.11 µmol/L, 95% CI - All-cause mortality
14.56 to 4.34). There were no significant differences in all-cause mortality (
Duration of hospital stay: measured in days Analysis 2.1; 2 trials; 200 participants; RR 5.00, 95% CI 0.25 to
No trials reported duration of hospital stay. 102.00; very low quality of evidence).
Subgroup analysis Number of participants who did not recover from hepatic en-
We performed subgroup analyses for the outcomes no-recov- cephalopathy
ery (Analysis 1.2) and plasma ammonia concentration (Analysis There was no significant difference in lack of recovery (Analysis
1.5) using the prespecified subgroups (Subgroup analysis and 2.2; 7 trials; 430 participants; RR 1.01, 95% CI 0.85 to 1.21; very
investigation of heterogeneity). We could not perform subgroup low quality of evidence).
analyses by MELD score, as most trials did not report this, or by Adverse events
risk of bias, as we judged most trials at high risk of bias. There was no significant difference between participants treated
No-recovery with probiotic and those treated with lactulose for adverse events
We detected no significant differences for the following subgroup when considering the development of overt hepatic encephalopa-
analyses: type of probiotic used, test for subgroup differences: Chi² thy (Analysis 2.3 (Analysis 2.3.1); 6 trials; 420 participants; RR
= 0.74, df = 2 (P = 0.69); grade of hepatic encephalopathy, test 1.17, 95% CI 0.63 to 2.17; very low quality of evidence), hospital-
for subgroup differences: Chi² = 3.56, df = 1 (P = 0.06); duration isation (Analysis 2.3 (Analysis 2.3.3); 1 trial; 80 participants; RR

0.33, 95% CI 0.04 to 3.07; very low quality of evidence), intoler- Duration of hospital stay: measured in days
ance leading to discontinuation (Analysis 2.3 (Analysis 2.3.4); 3 No trial reported duration of hospital stay.
trials; 220 participants; RR 0.35, 95% CI 0.08 to 1.43; very low Subgroup analysis
quality of evidence), or change of/or withdrawal from treatment We performed subgroup analyses for the outcome plasma ammo-
(Analysis 2.3 (Analysis 2.3.5); 7 trials; 490 participants; RR 1.27, nia concentration (Analysis 2.5) using the prespecified subgroups
95% CI 0.88 to 1.82; very low quality of evidence). (Subgroup analysis and investigation of heterogeneity).
Quality of life We did not perform subgroup analyses by MELD score as this was
There were no significant differences in quality of life scores be- not reported in most trials, nor by risk of bias as the majority of
tween participants treated with probiotic and those treated with the trials were at high risk of bias.
lactulose in change in Total SIP Score (Analysis 2.4 (Analysis Plasma ammonia
2.4.1); 1 trial; 69 participants; MD 0.65, 95% CI -1.13 to 2.43; We detected a significant difference for the subgroup analyses on
very low quality of evidence); change in SIP Psychological Score grade of hepatic encephalopathy, test for subgroup differences:
(Analysis 2.4 (Analysis 2.4.2); 1 trial; 69 participants; MD 0.48, Chi² = 5.22, df = 1 (P = 0.02); I² = 80.9%. We detected no
95% CI -1.04 to 2.00; very low quality of evidence), or change significant difference for the subgroup analyses on type of probiotic
in SIP Physical Score (Analysis 2.4 (Analysis 2.4.3); 1 trial; 69 used, test for subgroup differences: Chi² = 5.60, df = 3 (P = 0.13)
participants; MD 0.38, 95% CI -0.61 to 1.37; very low quality of (Table 2).
evidence). Quality of the evidence
Secondary outcomes In the analyses comparing probiotic versus lactulose (Summary of
Sepsis findings 2), we downgraded the quality of the evidence to very low
There were no reports of septicaemia attributable to probiotic in for all outcomes due to concerns that the included trials were at
any trial. high risk of bias, the results were inconsistent or imprecise or both,
Change in plasma ammonia concentration and because a surrogate marker was used for clinically important
There was no significant difference in plasma ammonia concen- outcomes.
tration overall (Analysis 2.5; 6 trials; 325 participants; MD -2.93 Heterogeneity
µmol/L, 95% CI -9.36 to 3.50; very low quality of evidence), at Heterogeneity was demonstrated for the outcome plasma ammo-
one month or less (Analysis 2.5 (Analysis 2.5.1); 5 trials; 248 par- nia concentration (Analysis 2.5) (Chi² = 11.87, df = 4 (P = 0.02);
ticipants; MD -4.30 µmol/L, 95% CI -13.17 to 4.56), or at three I² = 66%). Heterogeneity seemed largely attributable to the grade
months (Analysis 2.5 (Analysis 2.5.2); 1 trial; 77 participants; MD of hepatic encephalopathy, and it did not seem attributable to the
1.16 µmol/L, 95% CI -1.96 to 4.28). type of probiotic used (Table 2).

Probiotics for people with hepatic encephalopathy (Review) A D D I T I O N A L S U M M A R Y O F F I N D I N G S [Explanation]
Probiotic versus lactulose for people with hepatic encephalopathy
Patient or population: people with hepatic encephalopathy

Setting: inpatients
Intervention: probiotic
Comparison: lactulose
Outcomes Anticipated absolute effects* (95% CI) Relative effect No of participants Quality of the evidence Comments
(95% CI) (studies) (GRADE)
Risk with lactulose Risk with probiotic
All-cause m ortality Study population RR 5.00 200 ⊕

(f ollow-up: 1 m onth to (0.25 to 102.00) (2 RCTs) VERY LOW 1,2
2 m onths) 0 per 1000 0 per 1000
(0 to 0)
No-recovery (incom - Study population RR 1.01 430 ⊕

plete resolution of clin- (0.85 to 1.21) (7 RCTs) VERY LOW 2,3,4
ical sym ptom s) 521 per 1000 526 per 1000
(f ollow-up: 1 m onth to (443 to 630)
3 m onths)
M oderate
500 per 1000 505 per 1000

(425 to 605)
Adverse events - Overt Study population RR 1.17 420 ⊕

hepatic encephalopa- (0.63 to 2.17) (6 RCTs) VERY LOW 2,3,4
thy 81 per 1000 95 per 1000
(f ollow-up: 1 to 3 (51 to 177)
m onths)
M oderate
60 per 1000 70 per 1000

(38 to 129)
19
Adverse Study population RR 1.27 490 ⊕

events - Change of / or (0.88 to 1.82) (7 RCTs) VERY LOW ,2,3,4
withdrawal f rom treat- 160 per 1000 203 per 1000
m ent (141 to 291)
(f ollow-up: 1 m onth to
3 m onths) M oderate
114 per 1000 145 per 1000

(101 to 208)
Quality of lif e It is uncertain whether probiotics im prove quality - 69 ⊕

(f ollow-up: 1 m onth to of lif e because the available evidence is of very (1 RCT) VERY LOW 1,2
3 m onths) low quality
Plasm a am m onia con- - The m ean plasm a - 325 ⊕

centration (f inal and am m onia concentra- (6 RCTs) VERY LOW 2,3,4
change scores) (µm ol/ tion (f inal and change
L) scores) (µm ol/ L) in the
(f ollow-up: 1 m onth to intervention group was
3 m onths) 2.93 f ewer (9.36 f ewer
to 3.5 m ore)
* The risk in the intervention group (and its 95% conf idence interval) is based on the assum ed risk in the com parison group and the relative effect of the intervention (and its
95% CI).
CI: conf idence interval; RCT: random ised clinical trial; RR: risk ratio
GRADE Working Group grades of evidence

High quality: We are very conf ident that the true ef f ect lies close to that of the estim ate of the ef f ect.
M oderate quality: We are m oderately conf ident in the ef f ect estim ate: The true ef f ect is likely to be close to the estim ate of the ef f ect, but there is a possibility that it is
substantially dif f erent.
Low quality: Our conf idence in the ef f ect estim ate is lim ited: The true ef f ect m ay be substantially dif f erent f rom the estim ate of the ef f ect.
Very low quality: We have very little conf idence in the ef f ect estim ate: The true ef f ect is likely to be substantially dif f erent f rom the estim ate of ef f ect
1
Downgraded one f or serious concerns or two levels f or very serious concerns of im precision (sm all sam ples, very f ew events,
and wide conf idence intervals).
2 Downgraded one level f or serious concerns or two levels f or very serious concerns of trials judged as at high risk of bias
(m ajority of studies at high risk of bias).

20
3 Downgraded one level f or serious im precision (95% CI includes null ef f ects).
4 Downgraded one level f or serious concerns or two levels f or very serious concerns of inconsistency in results.
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21
DISCUSSION randomised clinical trials with improved methodological quality
and outcome data collection and data reporting are required to
fully establish the role of probiotics in hepatic encephalopathy.
Summary of main results The use of tools that quantify the statistical reliability of data across
cumulative meta-analysis such as Trial Sequential Analysis, TSA
We included 21 trials with a total of 1420 randomised partici-
2011, ought to be included in future updates (Wetterslev 2008;
pants. The trials used a variety of probiotics, although the most
Thorlund 2011). We also need to search data-bases of regulatory
commonly used probiotic was VSL#3, a proprietary name for a
authorities for additional trials.
group of eight probiotics. Duration of administration of the ex-
perimental intervention varied from 10 days to 180 days. We clas-
sified 19 of 21 trials as having a high risk of bias.
Probiotics may lead to little or no difference in mortality from Potential biases in the review process
any cause compared with no treatment. Probiotics probably im- This systematic review with meta-analysis was undertaken with
prove recovery from hepatic encephalopathy (as measured by reso- broad inclusion criteria to assess the totality of available evidence.
lution of symptoms) compared with no treatment. Probiotics may Our literature search was comprehensive and did not exclude tri-
prevent the development of overt hepatic encephalopathy com- als based on language of publication or publication status. We at-
pared with no treatment. The effects of probiotics on change of/ tempted to contact authors wherever trial data and methodology
or withdrawal from treatment is uncertain because the quality of were unclear. All data extraction and analysis was undertaken by
the evidence was very low. Quality of life may slightly improve for several authors working independently to minimise bias. Despite
patients treated with probiotic than with no intervention. Plasma these strengths, there were some limitations: for example, we were
ammonia concentration may decrease for patients treated with not blinded to authorship during data extraction and ’Risk of bias’
probiotic than with no intervention. No trial reported duration of assessment. While we did attempt to contact study authors, we
hospital stay. were not always certain that our messages were received, and we
It is uncertain whether probiotics are better than lactulose for did not attempt to make any further contact if we received no re-
the management of hepatic encephalopathy, because the available sponse to our initial emails. As stated above, we might have missed
evidence was of very low quality across all outcomes. There were trials by not searching databases of regulatory authorities, and we
no reports of septicaemia attributable to probiotic in any trial. did not control risks of random errors.
Overall completeness and applicability of

Agreements and disagreements with other
evidence
studies or reviews
The number of trials and randomised participants included in this
A review published in 2011 discusses the effects of prebiotics, pro-
review has substantially increased with this update. However, data
biotics, and synbiotics in minimal hepatic encephalopathy (Shukla
from some trials were only available in abstract form; outcomes
2011a). As our review did not evaluate the combination of pro-
were often inconsistently reported; and most trials were at high
biotics, prebiotics, and synbiotics, it is not possible to make di-
risk of bias and included few participants. There is thus limited
rect comparisons between the reviews. Of note, the Shukla 2011a
evidence for the use of probiotics as a treatment for people with
review was only able to locate two trials of probiotics including
hepatic encephalopathy. Overall, there is a large number of trials
participants with minimal hepatic encephalopathy, compared to
on probiotic use in cirrhosis (without confirmed diagnosis of hep-
the five trials in the previous version of our review (McGee 2011),
atic encephalopathy). We have not considered trials of primary
suggesting that we utilised a more sensitive search strategy.
or secondary prevention using probiotics as prophylaxis against
A 2011 meta-analysis found improvement in “clinical and
hepatic encephalopathy in the present review, which ought to be
biochemical parameters in patients with minimal hepatic en-
the subject of another systematic review. Also, trials on synbiotics
cephalopathy” and a “decrease the morbidity of clinical hepatic
should be considered for inclusion in the future alongside probi-
encephalopathy” (Tang 2011). However, that study used the time
otics as a separate subgroup to illustrate comparative efficacy.
of Number Connection Test as a surrogate for clinical resolution
of symptoms. In addition, they used a fixed-effect model, while
we used the random-effects model in our review.
Quality of the evidence A 2012 review published a study, Holte 2012, with results largely
Although compared to the original 2011 review the quantity of similar to the initial 2011 publication of our systematic review and
evidence has increased, the quality of evidence has lagged behind meta-analysis (McGee 2011).
and is far from optimal. Although there may be emerging evidence A meta-analysis published in 2015 included nine randomised clin-
for probiotic use, the quality of evidence for their use is low. Further ical trials comparing probiotic against placebo or no treatment

(Zhao 2015). The authors concluded that probiotics were “associ- alternative option; however, their benefits and harms are still un-
ated with improvement of minimal hepatic encephalopathy, pro- certain, and many fundamental questions concerning their use re-
phylaxis of overt hepatic encephalopathy, and reduction of SIP main. First, the benefits and harms of probiotics must be assessed
score and severe adverse events”, and our findings mirror these in randomised clinical trials with low risk of systematic errors
findings to some extent. They grouped serious adverse events as any (’bias’) and low risk of random errors (’play of chance’). Moreover,
of “minimal hepatic encephalopathy developing into overt hepatic it is unknown whether all probiotics are of equal effectiveness or
encephalopathy, hospitalisations, infections, or unrelated emer- what dose or duration of probiotic therapy is necessary for treat-
gency room (ER) visits”. However, we have separated these adverse ment. It is also unknown whether colonisation though multiple
events into subgroups, and found a significant difference favour- dosing is necessary for benefit or if a single dose of probiotic suf-
ing probiotics only for reducing the progression to overt hepatic fices (McGee 2010). Future research should take these factors into
encephalopathy, and not for the other serious adverse events. Fur- account and consider alternative study designs; for example, fac-
thermore, we have graded our findings to reflect the quality of torial trials would allow multiple comparisons to be made in one
the available evidence and the subsequent uncertainty around the trial. Future trials should also adhere to the International Society
results. In addition, due to the small sample sizes involved, ran- for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN)
dom error or chance findings may partly explain the observed dif- consensus statement, which makes recommendations for trials in
ferences. Our review did not address the issue of prophylaxis of people with hepatic encephalopathy (Bajaj 2011), as well as guide-
hepatic encephalopathy. lines for the nomenclature of hepatic encephalopathy (Vilstrup
Another 2015 meta-analysis of probiotic use in hepatic en- 2014; Allampati 2015). According to this new nomenclature, the
cephalopathy included observational data as well as randomised term ’covert hepatic encephalopathy’ is used to denote either ’min-
clinical trials, but found only 14 studies, where we have included imal hepatic encephalopathy’ or ’grade 1 hepatic encephalopa-
21 randomised clinical trials (Saab 2015). Saab and colleagues thy’ as per the West Haven criteria (Conn 1977). As the trials
found that when probiotics were compared with placebo, there included in this review typically pre-date the development of this
was a significant improvement in minimal hepatic encephalopa- new nomenclature, we have continued to use the term ’minimal
thy and decreased progression to overt hepatic encephalopathy, hepatic encephalopathy’ where this has been historically applied
which is consistent with our findings. This study also reported by the original study authors to describe their study group, in or-
no significant difference in improvement of minimal hepatic en- der to precisely represent the participants enrolled in those partic-
cephalopathy, hospitalisation rates, or progression to overt hepatic ular studies. Furthermore, we have used the term ‘acute hepatic
encephalopathy when probiotics were compared with lactulose, encephalopathy’ in our inclusion criteria as an inclusive term in
which is again consistent with our findings. However, the Saab order to select a broad range of studies. Any changes to the inclu-
study noted significantly decreased hospitalisation rates when pro- sion criteria based on the new nomenclature of ‘Type A hepatic
biotics were compared with placebo, which we did not. This is encephalopathy’ should be considered for the next review update.
likely due to bias from their observational data and incomplete The Human Microbiome Project is one important initiative that
evidence synthesis. will likely contribute to a better understanding of the complex
relationship between humans and microbes (Turnbaugh 2007).
The high response in the control groups of this review reflects the
natural history of hepatic encephalopathy, with its spontaneously
AUTHORS’ CONCLUSIONS fluctuating nature and possibility for spontaneous remission. Fu-
ture trials should take this into account when assessing the efficacy
Implications for practice of interventions. It is also important that those conducting trials
Due to the very low overall quality of the evidence, there is lim- also account for the time of day in which assessments are made.
ited evidence for the use of probiotics compared with lactulose. Consideration should be given to the type of placebo used, for ex-
Compared with placebo or no intervention, probiotics probably ample inactivated probiotic. All trials should at a minimum assess
improve recovery and may lead to improvements in the develop- important outcomes such as mortality, quality of life, and adverse
ment of overt hepatic encephalopathy, quality of life, and plasma events. Trials should also be designed according to Standard Pro-
ammonia concentrations, but may lead to little or no difference tocol Items: Recommendations for Interventional Trials (SPIRIT)
in mortality. Statement (www.spirit-statement.org/) and reported following the
CONSORT Statement (www.consort-statement.org/).
Implications for research Future systematic reviews on this topic ought to search also
Hepatic encephalopathy has a poor clinical outcome and is a sig- databases of regulatory authorities. Review authors should also use,
nificant burden on the healthcare system. Current treatment op- for example, Trial Sequential Analysis to control risks of random
tions are of limited efficacy. Probiotics represent an inexpensive errors.

ACKNOWLEDGEMENTS ish State is the largest single funder of the Cochrane Hepato-Bil-
iary Group through its investment in the Copenhagen Trial Unit,
We would like to thank The Cochrane Hepato-Biliary Group,
Centre for Clinical Intervention Research, Rigshospitalet, Copen-
especially Dimitrinka Nikolova and Sarah Klingenberg, for their
hagen University Hospital, Denmark. Disclaimer: The views and
advice and support.
opinions expressed in this review are those of the authors and do
We are very grateful to all the authors who responded to our not necessarily reflect those of the Danish State or the Copenhagen
queries and provided helpful information: JS Bajaj, C Loguercio, Trial Unit.
BC Sharma, RK Dhiman, R Nair, MK Lunia, and S Saji.
Peer reviewers: Kevin D Mullen, USA; Goran Bjelakovic, Serbia.
We are also very grateful to Anouk Bakens and Kerrie Wiley for
their work on the original review. Contact editors: Vanja Giljaca, Croatia; Christian Gluud, Den-
We are grateful to Sunny Wu for his translation services. mark.
Cochrane Review Group funding acknowledgement: The Dan- Sign-off editor: Christian Gluud, Denmark.
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prophylaxis of hepatic encephalopathy in cirrhosis: an Bajaj 2008a {published data only}
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∗
estimates in controlled trials with different interventions Indicates the major publication for the study

CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]
Bajaj 2008
Methods Design: a prospective randomised trial with open allocation

A 2:1 randomisation to the treatment arm was performed
Trial duration: 60 days
Treatment duration: 60 days
Participants Setting: outpatient single tertiary centre trial

Country: USA
Age range (years): 44 to 60
Total numbers randomised (group A/group B): 25 (17/8)
Sex (M/F): not stated
Language: English
Stage/severity of hepatic encephalopathy: Child-Pugh score A/B/C: 22/3/0.
Cause of hepatic encephalopathy: non-alcoholic aetiology of cirrhosis
Inclusions: non-alcoholic participants with cirrhosis with minimal hepatic encephalopa-
thy. Defined by no alcohol intake within 3 months of the trial and a non-alcoholic aeti-
ology of cirrhosis
Exclusions:
• Alcohol use within 3 months.
• Alcoholic aetiology of cirrhosis.
• Current psychoactive medication use.
• On current therapy for prevention or treatment of overt hepatic encephalopathy.
• Lack of English fluency.
• History of overt hepatic encephalopathy.
• Antibiotic use within 6 weeks of the trial.
• Diabetes mellitus.
Interventions Treatment group (A) probiotic yogurt:

1. Streptococcus thermophilus (log 9 CFU/g on Day 0) for 60 days.
2. Lactobacillus bulgaricus (log 8.7 CFU/g on Day 0) for 60 days.
3. Lactobacillus acidophilus and Lactobacillus casei (log 5.9 CFU/g on Day 0) for 60
days.
4. Bifidobacteria (log 5.2 CFU/g on Day 0) for 60 days.
Participants received 12 ounces of yogurt a day.
The specific probiotic used in this yogurt was Yo-Fast 88 manufactured by Chr-Hansen
Inc in Denmark.
Yogurt is manufactured by CC Jersey Crème, Spring Valley, Wisconsin
Control group (B): no treatment.
Outcomes 1. Minimal hepatic encephalopathy reversal.

2. Overt hepatic encephalopathy development.
3. Adherence.
4. Child-Pugh score.
5. MELD score.
6. SF-36 score.

Bajaj 2008 (Continued)
7. Venous ammonia.
8. IL-6 and TNF-alpha levels.
Notes Contacted Professor JS Bajaj on 14 October 2010, who provided additional information
Funding source: “The General Clinical Research Center at the Medical College of Wis-
consin sponsored by the NIH supported this study”. This study declared the funding
source and was deemed to be independently funded
Risk of bias Risk of bias
Bias Authors’ judgement Support for judgement
Sequence generation Low risk Adequate sequence generation. A 2:1 ran-

domisation was performed using a random
numbers table
Allocation concealment High risk The treatment allocation was not concealed
from the principal investigator
Blinding High risk Participants knew whether they were in the

Participants treatment group or the control group
Blinding High risk The investigator knew whether a participant

Personnel was included in the treatment group or the
control group
Blinding Low risk The outcome scorer was blinded.

Outcome assessors
Incomplete outcome data Low risk 3 out of 17 participants in the treatment

All outcomes group dropped out: 1 died from sepsis un-
related to the trial on day 67 but did not
come to his first visit, and 2 did not like the
taste and dropped out on days 13 and 17,
respectively
2 out of 8 participants in the control group
dropped out; they developed OHE on days
22 and 35
Primary analysis used an intention-to-treat
approach.
Selective outcome reporting Low risk All outcomes mentioned in the methods
(minimal hepatic encephalopathy reversal,
overt hepatic encephalopathy development,
and adherence) were described in the results
at baseline, after 30 days, and after 60 days.
Personal communication with the author re-
vealed no other outcomes were assessed

Bajaj 2008 (Continued)
Funding source Low risk The General Clinical Research Center at the
Medical College of Wisconsin sponsored by
the NIH supported this study
Bajaj 2014a
Methods Design: a parallel randomised trial

Trial duration: 8 weeks
Treatment duration: 8 weeks
Participants Setting: outpatient clinic setting

Country: USA
Age range (years): inclusion criteria 18 to 65 years; mean age (SD) in treatment group 56.
3 +/- 9.0, placebo group 58.4 +/- 4.3; range not specified
Total numbers randomised (treatment group/placebo group): 37 (18/19)
Sex (M/F): 25/12
Language: English
Stage/severity of hepatic encephalopathy: minimal hepatic encephalopathy, MELD score
(mean +/- SD of intervention, control group: 8.6 +/- 2.2, 8.3 +/- 2.0)
Cause of hepatic encephalopathy: cirrhosis due to HCV, HCV + alcohol, alcohol, NASH,
and other causes
Inclusions: “Patients with cirrhosis defined as having histological evidence or evidence
with radiology and endoscopy of cirrhosis whose disease had been stable for 6 months
without specific treatment changes, and were between the age range 18-65 were included.
”
Exclusions: “We excluded patients with an unclear diagnosis of cirrhosis, those who had
consumed alcohol within 6 months, those with an upper gastrointestinal bleeding episode
or need to be on systemic antibiotics within 6 weeks, those on current or past specific
treatment for HE, with hepatocellular cancer, with yogurt/probiotic consumption within
2 weeks, those with inflammatory bowel disease, history of pancreatitis, psychoactive
medication use (apart from chronic anti-depressants), with a recent absolute neutrophil
count <500/mm3 and those with liver transplant.”
Interventions Lactobacillus GG AT strain 53103, 3 batches of LGG and placebo were used. Each LGG
batch had > 50 billion CFU/g (51, 61, and 53, respectively), without any other organisms.
No live organisms were detected in the placebo batches
Outcomes 1. Detection of LGG in stool.

2. Serum and urine metabolomics.
3. Cognition and QoL.
4. Adverse events and serious adverse event.
Notes This study was carried out under the IND mechanism of Center for Biologics Evalua-
tion and Research (CBER) of the Food and Drug Administration (FDA) (IND number
BB13870)
Contacted Professor JS Bajaj on 14 March 2015, who provided additional information
Funding source: “JSB received funding from NCCAM, NIH grant U01AT004428 for
this trial. No other personal or funding interests exist. Writing and preparation of this

Bajaj 2014a (Continued)
paper was performed by the authors”. This study declared the funding source and was
deemed to be independently funded
Sequence generation Low risk “Subjects were then randomised into

placebo or LGG for 4 weeks using blocks of
4 created by the VCU Investigational Phar-
macy using a random sequence generator.”
Allocation concealment Low risk Treatment allocation only available to inves-

tigational pharmacy staff
Blinding Low risk Participants were blinded.

Participants
Blinding Low risk Personnel were blinded.

Personnel
Blinding Low risk Outcome assessors were blinded.

Outcome assessors
Incomplete outcome data Low risk “Thirty-seven patients were randomised.

All outcomes Two patients withdrew consent within the
first month due to logistic reasons without
any adverse events (both LGG group). One
additional patient had to be scheduled for
a splenic arterial embolisation for which he
would need antibiotics and narcotics (LGG
group) and was withdrawn before receiv-
ing medication. Four patients withdrew due
to infections or other contraindications to
continuation of the study [one broke her
wrist and needed antibiotics (placebo), one
had an asymptomatic urinary tract infection
based on urine collected before randomi-
sation with methicillin-sensitive Staphylo-
coccus aureus (placebo), two were found to
have dental issues within a week of randomi-
sation that needed antibiotics (one placebo
and one LGG)]”
Selective outcome reporting Unclear risk “Blood was collected for MELD score, am-
monia, serum albumin and pre-albumin,
and the dietician met with them to con-
firm continued adherence on the prescribed
diet. If there were no adverse events requir-

Bajaj 2014a (Continued)
ing discontinuation, the subjects were re-

prescribed their medication for another 4
weeks. The end-of-drug visit was carried out
4 weeks later (8 weeks after drug initiation)
where all procedures including physical ex-
amination, cognitive testing, HRQOL eval-
uation, dietary assessment, sample (blood,
urine, stool) collection and evaluation of ad-
herence and adverse events were performed.
”
Only information at the end of 8 weeks was
reported.
Funding source Low risk “JSB received funding from NCCAM, NIH
grant U01AT004428 for this trial. No other
personal or funding interests exist. Writing
and preparation of this paper was performed
by the authors.”
Dhiman 2013a
Methods Design: randomised parallel trial/double-blind, randomised, placebo-controlled study

Participants Setting: unspecified

Country: India
Age range (years): 45.5 to 52.5
Total numbers randomised: 80
Sex (M/F): 71/9
Language: unspecified
Stage/severity of hepatic encephalopathy: minimal hepatic encephalopathy
Cause of hepatic encephalopathy: unspecified
Inclusions: cirrhotics with MHE
Exclusions: unspecified
Interventions 40 participants received probiotic (1 sachet of VSL#3 (CD Pharma India Pvt. Ltd, New
Delhi), at a dose of 900 billion bacteria daily, and 40 participants received placebo
Outcomes 1. Reversal of MHE.

2. Figure connection test-A.
3. Digit symbol test.
4. Plasma IL-6.
5. Plasma oxindole.
6. Plasma ammonia.
7. MCS of SF-36 HRQOL.
8. Adverse events/serious adverse event.

Dhiman 2013a (Continued)
Notes Clinical Trials Registry - India /2008/091/000268

Contacted Professor RK Dhiman on 22 December 2014. Awaiting additional information
from author
Funding source: abstract only, unable to assess funding source
Sequence generation Unclear risk Abstract only, unable to assess
Allocation concealment Unclear risk Abstract only, unable to assess
Blinding Unclear risk Abstract only, unable to assess

Participants

Personnel

Outcome assessors
Incomplete outcome data Unclear risk Abstract only, unable to assess

All outcomes
Selective outcome reporting Unclear risk Abstract only, unable to assess
Funding source Unclear risk Abstract only, unable to assess
Liu 2004
Methods Design: a parallel-group randomised trial

Study duration: unknown
Participants Setting: outpatient

Country: China
Total numbers randomised (group A/group B/group C): 55 (20/20/15)
Group C was not relevant to our analysis.
Sex (M/F): 53/2
Language: English
Stage/severity of hepatic encephalopathy: Child-Pugh score A/B+C: 8/47
Cause of hepatic encephalopathy: people with cirrhosis and hepatic encephalopathy with-
out known precipitants of hepatic encephalopathy such as renal impairment, alcohol-
related hepatic encephalopathy, complicating hepatocellular carcinoma, etc
Inclusions:

Liu 2004 (Continued)
• Cirrhotic patients with minimal hepatic encephalopathy, without over hepatic

encephalopathy.
• People who had been abstinent from alcohol for at least 2 months, as corroborated
by family members or caregivers or both.
Exclusions:
• Histological features of alcoholic hepatitis.
• A history within the previous 6 weeks of factors including infection, treatment with
antibiotics, lactulose or immunomodulatory drugs, and gastrointestinal haemorrhage.
• Other causes of reversible hepatic functional decompensation such as drug-related
hepatotoxicity and choledocholithiasis.
• Other known precipitants of hepatic encephalopathy, including renal impairment,
electrolyte imbalance, and complicating hepatocellular carcinoma.
Interventions Treatment group (A)

Oral supplementation with a synbiotic preparation containing Pediacoccus pentosaceus,
Leuconostoc mesenteroides, Lactobacillus paracasei, and Lactobacillus plantarum (each pro-
biotic at 1010 CFUs/day, total dose of probiotics in a day: 4 x 1010 CFUs) plus 10 g of
bioactive fermentable fibre (2.5 g beta glucan, 2.5 g inulin, 2.5 g pectin, 2.5 g resistant
starch) for 30 days
Treatment group (B)
10 g of bioactive fermentable fibre (2.5 g beta glucan, 2.5 g inulin, 2.5 g pectin, 2.5 g
resistant starch) for 30 days
Control group (C)
Placebo (non-fermentable fibre) for 30 days.
Outcomes 1. Faecal pH.

2. Venous ammonia levels.
3. Serum endotoxin levels.
4. Minimal hepatic encephalopathy status.
6. Adverse events.
7. Overt hepatic encephalopathy development.
Notes Contacted Dr Q Liu on 15 October 2010, received no response.

Funding source: not stated
Sequence generation High risk 1 sachet was randomly drawn from a pool
for each participant, which is equivalent to
drawing lots. We feel that this does not rep-
resent best practise for randomisation, and
so have judged this category as high risk of
bias according to our predefined criteria
Allocation concealment Low risk Sachets were coded and contents unknown
to investigators when drawn

Liu 2004 (Continued)
Blinding Unclear risk Not stated for participants

Participants
Blinding Unclear risk Which sachets (A, B, or C) contained

Personnel the synbiotic, fermentable fibre or non-fer-
mentable fibre preparations was unknown
to the investigators until after the study had
been completed and results had been anal-
ysed
Blinding Unclear risk Not stated for outcome assessors

Outcome assessors
Incomplete outcome data Unclear risk Unclear from the study

All outcomes
Selective outcome reporting Unclear risk Unclear from the study
Funding source Unclear risk Not stated
Loguercio 1987
Methods Design: a parallel-group randomised trial

Study duration: 23 days

Country: Italy
Sex (M/F): 26/14
Language: English
Stage/severity of hepatic encephalopathy: grade I or II
Cause of hepatic encephalopathy: alcohol, hepatitis, cirrhosis
Inclusions: cirrhotic patients with non-advanced hepatic encephalopathy (grade I or II)
Exclusions:
• HE degree > 2.
• Alcohol use at the moment of the study.
• Mental disorders or benzodiazepine use or both.
• Non-compliance.

Enterococcus lactic acid bacteria strain SF68 (2 capsules, each containing 75 x 106 CFUs,
3 times daily, for 10 days). Bioflorin is a trade name of Giuliani and is distributed by
Gipharmex SpA, Italy
Control group (B)
30 mL lactulose 4 times daily, for 10 days.

Loguercio 1987 (Continued)
Outcomes 1. Mental state.

2. Bowel function.
3. Presence/absence abdominal pain.
4. Blood ammonia level.
5. Presence/absence meteorism.
6. Reitan’s test (Number Connection Test).
7. Adverse events.
Notes Additional information on ’Risk of bias’ criteria provided by the author. Contacted Pro-
fessor C Loguercio on 15 October 2010
Funding source: “Gipharmex (Milan, Italy) supported this study”. This study declared the
funding source and was deemed to be industry funded
Sequence generation Unclear risk Participants were randomly assigned to a

treatment group. No further information
about randomisation
Allocation concealment Unclear risk Information not provided
Blinding Low risk Participants were blinded.

Participants
Blinding Low risk Personnel were blinded.

Personnel
Blinding Low risk The outcome scorer was blinded.

Outcome assessors
Incomplete outcome data High risk All participants completed the treatment
All outcomes period. 5 participants given lactulose and
4 given Enterococcus SF68 did not arrive
for post-treatment follow-up. On day 15, 2
participants given lactulose were withdrawn
from the study because of marked hyperam-
monaemia and a worsening of hepatic en-
cephalopathy
Selective outcome reporting Unclear risk Unclear from study
Funding source High risk Gipharmex (Milan, Italy) supported this

study.

Loguercio 1995
Methods Design: randomised parallel trial

Treatment duration: 3 periods of 4 weeks
Participants Setting: outpatient setting

Country: Italy
Sex (M/F): 26/14
Stage/severity of hepatic encephalopathy: grade 1 to 2 hepatic encephalopathy
Cause of hepatic encephalopathy: alcoholic/other: 21/19
Inclusions: “Forty patients with cirrhosis, with low grade 1-2 hepatic encephalopathy of
the chronic recurrent type and ammonia plasma levels above 59 uM (normal values: < 44
uM) were considered suitable for the study.”
Exclusions: “Exclusion criteria in the selection of patients included the presence of one of
these pathologies: grade 3-4 hepatic encephalopathy, ascites that needed treatment with
furosemide, alcohol abuse or recent abstinence (<6 months), liver tumour, and hepatore-
nal syndrome. We also excluded patients with severe sight disorders, colour blindness,
alterations of the eye fundus and disorders of the anterior segment.”
Interventions Participants entered a 15-day run-in period. 1 group of participants took, after main meals,
2 capsules containing a total of 150 million Enterococcus faecium strain SF68 3 times a day
for 4 weeks; the participants in the lactulose treatment branch ingested, after main meals,
30 mL (20 g) oral lactulose 3 times a day for the same time span. The treatment was
repeated for three 4-week periods, each separated by a 2-week wash-out interval. During
the 2-week wash-out period participants were treated as during the run-in period
Outcomes 1. Arterial ammonia concentration.

2. NCT score.
3. Mental state.
4. Encephalopathy Global Score.
5. Flash evoked visual potentials.
Notes Contacted Professor C Loguercio on 7 June 2015, received no response

Sequence generation Low risk “After the basal evaluation, the patients
enrolled in the study were assigned to
one of two treatments according the Broc
Plan computerised randomisation scheme
(kindly provided by the Biometrics Division
of Bracco SPA).”

Loguercio 1995 (Continued)
Allocation concealment Low risk Computer randomisation was provided by

external providers.
Blinding Unclear risk Unclear from the study

Participants

Personnel

Outcome assessors
Incomplete outcome data High risk 21 participants were initially randomised to

All outcomes SF68 and 19 to lactulose group
“Seven patients in the lactulose group inter-
rupted the treatment: one because of diar-
rhoea and fever during the second period,
two because of drug intolerance with diar-
rhoea (one during the second period and
one during the third period), and four be-
cause of deterioration of the neurological
state (one during the first period, two dur-
ing the first wash-out period, and one dur-
ing the second period). Therefore, only 14
patients treated with SF68 and 11 treated
with lactulose completed the study.”
Selective outcome reporting Unclear risk Unclear from the study
Funding source Unclear risk Unclear from the study
Lunia 2014
Methods Design: parallel randomised trial

Trial duration: mean follow-up of group 1 participants was 38.6 ± 8.80 weeks and group
2 participants was 34.3 ± 9.8 weeks
Treatment duration: 3 months

Country: India
Age range (years): range unspecified, mean (SD): 46.6 (13.1)
Sex (M/F): 47/28
Cause of hepatic encephalopathy: unspecified in abstract
Inclusions: unspecified in abstract
Exclusions: unspecified in abstract

Lunia 2014 (Continued)
Interventions Cirrhotic patients with MHE were divided into: group 1 (probiotics, n = 42, VSL#3) and
group 2 (control, n = 39)
Outcomes All participants underwent psychometric tests, critical flicker frequency, glucose hydrogen
breath test for SIBO and lactulose hydrogen breath test for OCTT.
Primary endpoint was reversal of MHE.
Mortality.
Arterial ammonia.
Small intestinal bowel overgrowth.
Orocaecal transit time.
Notes Contacted Dr Manish Lunia on 22 December 2014. Awaiting additional information

from author
Funding source: abstract only, unable to assess funding source

Participants

Personnel

Outcome assessors

All outcomes
Malaguarnera 2010
Methods Design: a double-blind, parallel-group randomised trial

Study duration: 2004 to 2007
Participants Setting: inpatient

Country: Italy

Malaguarnera 2010 (Continued)
Age range (years): not stated

Sex (M/F): 62/63
Language: English
Stage/severity of hepatic encephalopathy: Child-Pugh score A/B/C: 46/59/20
Cause of hepatic encephalopathy: chronic hepatitis and cryptogenic cirrhosis with spon-
taneous hepatic encephalopathy
Inclusions:
• Chronic hepatitis with spontaneous manifest hepatic encephalopathy (mental state
grade I or II according to the West Haven criteria) and a Number Collection Test-A
performance time > 30 seconds.
• Hyperammonaemia (venous ammonia concentration > 50 mmol/L).
• Co-operative, hospitalised, adult patients with liver cirrhosis diagnosed by clinical,
histological, and ultrasonographic findings (reduced dimensions of the liver as well as
splenomegaly) and oesophageal varices (stages II or III) observed by endoscopy.
Exclusions:
• Major complications of portal hypertension, such as gastrointestinal blood loss,
hepatorenal syndrome, or bacterial peritonitis.
• Acute superimposed liver injury.
• Other neurological disease and metabolic disorders such as alcoholism, diabetes
mellitus, unbalanced heart failure and/or respiratory failure or end-stage renal disease.
• Severe hepatic encephalopathy (mental state grade III to IV).
• Administration of anti-hepatic encephalopathy medications such as neomycin,
branched-chain amino acids.
• Any additional precipitating factors such as high protein intake (additional high-
protein meals), constipation, or intake of psychostimulants, sedatives, antidepressants,
benzodiazepines or benzodiazepines antagonists (flumazenil).
• Fever, sepsis, or shock were also excluded to avoid variations caused by body
temperature.

Bifidobacterium (subtype not stated) + (FOS) fructo-oligosaccharides for 60 days (dose
not stated)
Control group (B)
Lactulose for 60 days (dose not stated).
Note: FOS and lactulose were considered comparable because they are both complex car-
bohydrates, which are indigestible to humans but digestible to bacteria. We were unable to
locate any efficacy data comparing FOS to lactulose in people with hepatic encephalopathy
Outcomes 1. Trail Making Test.

2. Cognitive functions.
3. Grade of hepatic encephalopathy.
Notes Contacted Dr M Malaguarnera on 15 October 2010, received no response


Malaguarnera 2010 (Continued)
Sequence generation Low risk Randomisation was based on a computer-

generated list.
Allocation concealment Unclear risk Unclear from study
Blinding Unclear risk Stated it was a double-blind trial, but not

Participants for whom.
Blinding Unclear risk Stated it was a double-blind trial, but not

Personnel for whom.
Blinding Unclear risk Not stated for outcome assessors

Outcome assessors
Incomplete outcome data Unclear risk Unclear from study

All outcomes
Mittal 2009

Study duration: October 2007 to October 2009

Country: India
Total numbers randomised (group A/group B/group C/group D): 160 (40/40/40/40)
We did not use group B and D in our analysis, as these were not useful to compare to
probiotics.
Sex (M/F): 123/37
Language: English
Stage/severity of hepatic encephalopathy: not stated
Cause of hepatic encephalopathy: cirrhosis due to alcoholic liver disease, hepatitis B,
hepatitis C, or other causes
Inclusions: people with cirrhosis who have minimal hepatic encephalopathy, diagnosed
by 2 or more abnormal (+2SD from the mean) psychometric tests
Exclusions:
• Overt HE based on detailed neurological examination or history of overt HE in
past 6 weeks.
• Recent history (< 6 wk) of gastrointestinal bleed.
• Active ongoing infection.
• Renal impairment with serum creatinine > 1.5 mg %.

Mittal 2009 (Continued)
• Electrolyte impairment (serum sodium < 130 or > 150 meq/dL, serum potassium <
3.0 or > 5.5 meq/dL).
• Recent alcohol use (< 6 wk) as reported by the person, recent use of antibiotic,
lactulose, or LOLA (< 6 wk), use of psychotropic drugs in last 6 weeks.
• TIPS, shunt surgery.
• Hepatocellular carcinoma.
• Severe comorbidity such as congestive heart failure, pulmonary disease,
neurological and psychiatric problems impairing quality of life, or poor vision
precluding neuropsychiatric assessment.
Interventions Control group (A)

No treatment.
Treatment group (B)
30 mL to 60 mL lactulose twice daily for 3 months.
Treatment group (C)
VSL#3 (containing Streptococcus thermophilus, Bifidobacterium breve, Bifidobacterium
longum, Bifidobacterium infantis, Lactobacillus acidophilus, Lactobacillus plantarum, Lacto-
bacillus paracasei, Lactobacillus bulgaricus) 110 billion CFUs twice daily for 3 months.
Treatment group (D)
6 g (LOLA) L-ornithine L-aspartate 3 times daily for 3 months
Outcomes 1. Minimal hepatic encephalopathy recovery.

2. Minimal hepatic encephalopathy improvement.
3. Arterial ammonia level.
4. Development of overt hepatic encephalopathy.
5. Sickness Impact Profile Score (quality of life).
Notes Author provided additional information on ’Risk of bias’ criteria. Contacted Professor BC
Sharma on 14 October 2010.
Author provided unpublished data.
Sequence generation Low risk Participants were randomised to 1 of the

treatment groups using computer-generated
random tables
Allocation concealment Low risk “The sequences were concealed until a de-
cision to enroll a patient was taken after as-
sessment for eligibility and after receiving
informed consent.”
Blinding High risk Different way of administering for ev-

Participants ery treatment, therefore participants knew
which treatment they had received

Mittal 2009 (Continued)
Blinding High risk Compliance was assessed primarily using

Personnel pill and bottle count, therefore blinding was
not possible
Blinding High risk Compliance was assessed primarily using

Outcome assessors pill and bottle count, therefore blinding was
not possible
Incomplete outcome data Unclear risk 11 participants were lost to follow-up, 3

All outcomes from group A, 1 from group B, 3 from group
C, and 4 from group D. During treatment,
7 participants had to be admitted to the hos-
pital for causes other than overt hepatic en-
cephalopathy. Of these 7 participants, 2 par-
ticipants died, 1 each in group A and D
Primary analysis used an intention-to-treat
approach, probably with imputation
Selective outcome reporting Unclear risk Unclear from the trial
Mouli 2014
Methods Design: randomised controlled trial

Trial duration: 2 months
Participants Setting: tertiary care medical centre

Country: India
Age range (years): range unspecified, mean (SD): lactulose group 44.2 (10.4); probiotic
group 39.6 (11.4)
Sex (M/F): 110/10
Language: English
Stage/severity of hepatic encephalopathy: minimal hepatic encephalopathy; CTP (A/B/
C): probiotics group (14/24/22); lactulose group (15/30/15)
Cause of hepatic encephalopathy: alcoholic/viral/other: probiotics group (24/24/12); lac-
tulose group (21/24/15)
Inclusions: The inclusion criterion was the diagnosis of MHE in people with cirrhosis
aged between 15 and 80 years
Exclusions: “The exclusion criteria were: history of overt HE in the past 6 weeks; history of
intake of lactulose or probiotics or antibiotics within the past 6 weeks; presence of any other
neurological or psychiatric diseases; history of undergoing shunt surgery or transjugular
intrahepatic portosystemic shunt for portal hypertension; currently on medications which
were likely to interfere with psychometric performance; history of alcohol intake during
the past 6 weeks; history of gastrointestinal bleeding or spontaneous bacterial peritonitis
in the past 6 weeks; presence of hepatocellular carcinoma, renal failure or portal vein

Mouli 2014 (Continued)
thrombosis; presence of significant co-morbidities such as diabetes, congestive heart failure,

chronic respiratory disease, chronic kidney disease or malignancy; and visual impairment
and refusal for consent.”
Interventions Participants were randomised to receive either lactulose (Lark Laboratories; Rajasthan,
India) or probiotics (VSL#3; Sun Pharmaceutical, Mumbai, India) for a period of 2
months. Lactulose was given at a dose of 30 to 60 mL/day orally to ensure 2 to 3 soft stools
per day. VSL#3 was given at a dose of 4 capsules (2 twice a day) per day, amounting to a total
of 450 billion CFU/day; each capsule contained 112.5 billion viable lyophilised bacteria of
4 strains of Lactobacillus (L acidophilus DSM 24735, L plantarum DSM 24730, L paracasei
DSM 24733, L delbrueckii subsp. bulgaricus DSM 24734), 3 strains of Bifidobacterium
(B longum DSM 24736, B breve DSM 24732, B infantis DSM 24737), and 1 strain of
Streptococcus (S thermophilus DSM 24731).
Outcomes The primary outcome measure was improvement of MHE, which was defined as the
normalisation of the prior abnormal neuropsychometric/neurophysiological tests. The
secondary outcome measure was change in venous ammonia level with study intervention.
The study endpoints were: (i) completion of 2 months of treatment; (ii) development of
overt HE; and (iii) death
Notes Trial ID: NCT01008293

Contacted Dr VP Mouli on 14 March 2015, received no response
Funding source: “We thank the Indian Council of Medical Research (ICMR) for provid-
ing a research grant and CD Pharmaceuticals India for providing probiotic VSL#3 and
lactulose”. This study declared the funding source and was deemed to be independently
funded
Sequence generation Low risk “Block randomization was used to allo-

cate the patients to lactulose and probiotics
groups. The random numbers were gener-
ated using Stata software (StataCorp, Col-
lege Station, TX, USA).”
Allocation concealment Low risk “Allocation of the patients to receive the

study intervention drugs was done by using
the sequentially numbered, opaque, sealed
envelope method. The envelopes were pre-
pared by a statistician not associated with
the conduct of the study, and were opened
sequentially only after the patient’s name,
age and sex were written on them by a per-
son not associated with the study.”

Mouli 2014 (Continued)
Blinding High risk The study was limited by being an open-

Participants label trial with a relatively small sample size
with a short period of intervention. Blinding
was not possible due to the differences in
physical state between the drugs
Blinding High risk The study was limited by being an open-

Personnel label trial with a relatively small sample size
with a short period of intervention. Blinding
was not possible due to the differences in
physical state between the drugs
Blinding Low risk The objective nature of the tests for MHE
Outcome assessors would likely limit the effect of bias on MHE
recovery outcomes and venous ammonia
Incomplete outcome data Unclear risk “60 patients each were randomized into the
All outcomes lactulose and probiotics groups. Four pa-
tients were dropouts and 19 were lost to
follow up, two patients died and 22 devel-
oped overt encephalopathy, and hence dis-
continued with the trial drugs due to differ-
ent management protocols for overt HE. At
the end of intervention (i.e. at 2 months)
, 40 patients in the lactulose group and 33
patients in the probiotics group were taken
for analysis who had completed the study
medications.”
Selective outcome reporting Low risk Outcomes were reported as per protocol
found registered at ClinicalTrials.gov iden-
tifier NCT01008293
Funding source Low risk “We thank the Indian Council of Medical
Research (ICMR) for providing a research
grant and CD Pharmaceuticals India for
providing probiotic VSL#3 and lactulose”
Nair 2008

Trial duration: September 2006 to March 2007 (7 months)
Participants Setting: Study was conducted in Department of Neurology, Medical College Calicut, in
collaboration with Department of Gastroenterology
Country: India
Age range (years): range unspecified, mean 49.5 ± 8.05 SD

Nair 2008 (Continued)

Sex (M/F): M:F ratio 1:0.05
Language: English
Stage/severity of hepatic encephalopathy: MHE (Child A 14, Child B 26)
Cause of hepatic encephalopathy: alcohol 29, cryptogenic 10, HBV-related 1
Inclusions:
• Cirrhosis diagnosed by clinical/USG/biopsy.
• Minimal hepatic encephalopathy diagnosed by Number Connection Test-A and
evoked response tests - auditory and visual.
Exclusions:
• Clinically evident hepatic encephalopathy.
• Neurological diseases.
• Alcohol-free period of less than 2 months.
• Coexistent gastrointestinal haemorrhage.
• Renal impairment and electrolyte disturbances.
• Severe visual or auditory abnormalities.
Interventions Group A was given probiotic preparation in a dose of 1-gram sachet containing not less
than 1.25 billion cells of Lactobacillus acidophilus, Lactobacillus rhamnosus, Bifidobacterium
longum, and Saccharomyces boulardii 3 times daily after meals, and group B was given
placebo powder in identically looking sachet in a similar dose
Outcomes Number Connection Test-A, arterial ammonia, auditory evoked response tests, visual
evoked response tests
Notes Contacted Dr R Nair on 22 December 2014, full manuscript provided, awaiting additional
information from author
Funding source: “Sachets of drug as well as placebo were supplied by Aristo pharmaceuticals
Pvt. Ltd. No financial aid of any form was received from any source for the purpose of
conducting this trial”. This study declared the funding source and was deemed to be
independently funded
Sequence generation Low risk Randomisation was done using random ta-
ble allocation.
Allocation concealment Low risk Treatment allocation was concealed from in-
dividual who did the allocation
Blinding Low risk “The patients, examiners and investigators

Participants were blinded as to who is receiving the drug
and who receives placebo”

Personnel were blinded as to who is receiving the drug

Nair 2008 (Continued)

Outcome assessors were blinded as to who is receiving the drug
Incomplete outcome data Low risk 1 dropout in group A and 2 dropouts in

All outcomes group B;
“There were 3 drop outs (Group A - 1,
Group B - 2) - one in group A was lost to fol-
low up, so was one in group B. Second pa-
tient in Group B decided to withdraw from
study due to personal reasons.”
Selective outcome reporting Unclear risk Unable to assess
Funding source Low risk Sachets of drug as well as placebo were sup-
plied by Aristo Pharmaceuticals Pvt. Ltd
No financial aid of any form was received
from any source for the purpose of conduct-
ing this trial
Pereg 2011

Study duration: unclear

Country: Israel
Sex (M/F): unclear
Language: English
Cause of hepatic encephalopathy: cirrhosis due to alcoholic liver disease, hepatitis B,
hepatitis C, or other causes
Inclusions: people with liver cirrhosis and at least 1 major complication of cirrhosis in the
past, clinical evidence of portal hypertension, or decreased hepatic synthetic function
Exclusions:
• Any sign of decompensation from any precipitant including gastrointestinal
bleeding, infections, acute renal failure, electrolyte impairment, or hepatocellular
carcinoma.
• Those chronically treated with antibiotics or lactulose.
• People with alcoholic cirrhosis, for whom alcohol abstinence for at least 2 months
prior to enrolment could not be confirmed.

Wheat-based non-fermentable fiber placebo.
Treatment group (B)

Pereg 2011 (Continued)
Lactobacillus acidophilus, Lactobacillus bulgaricus, Bifidobacterium bifidum, and Streptococ-

cus thermophilus (Bio Plus, Supherb, Israel), each at a daily dose of 2 x 1010 CFUs.
Outcomes 1. Plasma ammonia.

2. Adverse events.
Notes The study was registered in ClinicalTrials.gov (ID: NCT00312910)

Funding source: “Supported by Supherb Ltd, Israel”. This study declared the funding
source and was deemed to be industry funded
Sequence generation Unclear risk Not stated
Allocation concealment Unclear risk Not stated
Blinding Unclear risk Only stated in the title that the trial was dou-
Participants ble-blinded - no specific details provided on
who was blinded or how blinding was con-
ducted
Personnel ble-blinded - no specific details provided on
ducted
Outcome assessors ble-blinded - no specific details provided on
ducted
Incomplete outcome data High risk Four participants “dropped out”, no further
All outcomes details provided
Funding source High risk Supported by Supherb Ltd, Israel.

Qiao 2010

Trial duration: There was a follow-up every 1to 2 weeks until treatment ended in which
the incidence of hepatic encephalopathy was recorded
Treatment duration: Treatment lasted for 24 weeks, and there was a follow-up every 1
to 2 weeks until treatment ended in which the incidence of hepatic encephalopathy was
recorded
Participants Setting: Laiyang Central Hospital, Yantai

Country: China
Age range (years): age range from 37 to 70, average age was 53.4
Sex (M/F): of the 64 participants, 51 were male and 13 were female
Language: Mandarin
Stage/severity of hepatic encephalopathy: diagnosed with subclinical hepatic encephalopa-
thy (SHE) and recruited for this study after intelligence testing
Cause of hepatic encephalopathy: 54 cases were cirrhosis from hepatitis B, 6 cases were
alcoholic cirrhosis, 1 case was primary biliary cirrhosis, 1 case was Budd-Chiari syndrome,
and 2 cases were of unknown cause
Inclusions: “Inclusion criteria: between August 2004 and August 2008, of all the patients
diagnosed with cirrhosis, 64 of them we diagnosed with SHE and recruited for this study
after intelligence testing. Cirrhosis diagnosis was based on history, clinical assessment,
laboratory findings, ultrasound, and CT scan investigations.”
Exclusions: “Exclusion criteria:
1. Currently or previously diagnosed with hepatic encephalopathy.
2. Patients with psychological or neurological disease.
3. Use of any sedatives or CNS depressants in the past 4 weeks.
4. Any GI bleeding, electrolyte/acid-base disturbances in the past 2 weeks.
5. Patients with alcoholic cirrhosis and continue to drink alcohol.”
Interventions Control group was given compound vitamin B tablets, 2 tablets each time, 3 times a day.
Treatment group was given bifid triple viable, 2 tablets each time, 3 times a day
Outcomes Outcome measurements: Blood ammonium, ALT, and NCT were measured 1 day before
treatment and again 1 day after treatment. NCT used the NCT-A version, where the
patient orders the numbers 1 to 25 and the time it takes to complete the test is recorded,
including time spent correcting any mistakes. NCT was measured in seconds; longer time
to complete indicates abnormality
Notes We could not find author contact details.

Sequence generation Unclear risk Unclear from the trial
Allocation concealment Unclear risk Unclear from the trial

Qiao 2010 (Continued)
Blinding Unclear risk Unclear from the trial

Participants

Personnel

Outcome assessors
Incomplete outcome data Unclear risk Unclear from the trial

All outcomes
Funding source Unclear risk Unclear from the trial
Saji 2011
Methods Design: a parallel randomised trial/randomised double-blind, placebo-controlled trial

Participants Setting: unclear

Country: India
Age range (years): range unclear, mean age (SD) treatment group/placebo group: 50.6 (5.
81)/52.15 (0.18)
Total numbers randomised: total (probiotic/placebo): 43 (21/22)
Sex (M/F): 37/3 excluding dropouts
Stage/severity of hepatic encephalopathy: stable cirrhotics in Child’s grade A and B (di-
agnosed clinically, by ultrasonography or biopsy) with minimal hepatic encephalopathy
diagnosed by NCT and evoked responses
Cause of hepatic encephalopathy: Aetiology of cirrhosis was alcohol in the majority of
participants (34/40). Other causes included hepatitis B in 2 participants, hepatitis C in 1
participant, and cryptogenic in 3 participants
Inclusions: Stable cirrhotics in Child’s grade A and B (diagnosed clinically, by ultrasonog-
raphy or biopsy) and having minimal hepatic encephalopathy as per the NCT-A and
evoked responses (auditory and visual) were included
Exclusions: “Those with clinically evident hepatic encephalopathy, neurological disease,
alcohol free period of less than 2 months, coexistent gastrointestinal hemorrhage, renal
impairment, electrolyte disturbances and those with severe visual or auditory abnormalities
were excluded from the study.”
Interventions Group A received probiotic preparation in a dose of 1-gram sachet containing not less than
1.25 billion spores of Lactobacillus acidophilus, Lactobacillus rhamnosus, Bifidobacterium
longum, and Saccharomyces boulardii, 3 times daily after meals. Group B received placebo
powder in identical-looking sachet 3 times daily after meals. The duration of treatment
was 4 weeks

Saji 2011 (Continued)
Outcomes At the end of 4 weeks, participants’ symptoms were recorded and a thorough examination
was done for any features of overt encephalopathy. Investigations were done to reassess
the Child’s score. Arterial ammonia, NCT -A, and evoked responses were repeated
Notes Both sachets of probiotics and placebo were supplied by Aristo Pharmaceuticals Pvt. Ltd
Mumbai
Contacted Dr S Saji on 14 March 2015, awaiting additional information from author
Sequence generation Low risk “Randomization was done using random ta-
ble allocation.”
Blinding Low risk “Group B received placebo powder in iden-

Participants tical looking sachet”
Blinding Unclear risk “The patients were randomized to two

Personnel groups and the drugs were administered in
a double blind fashion.”
Blinding Low risk Unclear from study, although the objective

Outcome assessors nature of the tests for MHE would likely
limit the effect of bias on MHE recovery
outcomes and venous ammonia
Incomplete outcome data Low risk “There were 3 drop-outs, one in the probi-
All outcomes otic group and two in the placebo group.”
“The data reported are only for the intent-
to-treat population.”
Selective outcome reporting Low risk “At the end of 4 weeks patients symptoms
were recorded and a thorough examina-
tion was done for any features of overt en-
cephalopathy. Investigations were done to
reassess the Child’s score. Arterial ammonia,
number connection test-A and evoked re-
sponses were repeated.”
All of the above outcomes except the Child’s
score were reported
Funding source Unclear risk “Sachets of probiotics as well as placebo were

supplied by Aristo pharmaceuticals Pvt. Ltd
Mumbai.”

Sharma 2008
Methods Design: open-label randomised trial

Treatment duration: 1 month
Time period: February 2005 to August 2006
Participants Setting: India

Total numbers randomised (group A/group B/group C): 105 (35/35/35)
Sex (M/F): 79/26
Language: English
Stage/severity of hepatic encephalopathy: Child-Pugh score A/B/C: 36/39/30
Cause of hepatic encephalopathy: cirrhosis due to alcohol consumption, chronic hepatitis,
and cryptogenic cirrhosis
Inclusions: cirrhotic patients with minimal hepatic encephalopathy without overt en-
cephalopathy
Exclusions:
• The presence of overt hepatic encephalopathy or history of hepatic encephalopathy.
• History of taking lactulose or any antibiotics.
• Alcohol intake.
• Gastrointestinal haemorrhage or spontaneous bacterial peritonitis during the past 6
weeks.
• Earlier transjugular intrahepatic portosystemic shunt or shunt surgery.
• Significant comorbid illness such as heart failure, respiratory failure, or renal failure.
• Any neurologic diseases such as Alzheimer’s disease, Parkinson’s disease, and non-
hepatic metabolic encephalopathies.
• Colour blindness and mature cataract, diabetic retinopathy, and people on
psychoactive drugs such as antidepressants or sedatives.

30 mL to 60 mL lactulose/day for 1 month.
Treatment group (B)
1 capsule (containing Enterococcus faecalis, Clostridium butyricum, Bacillus mesentericus,
Lactic acid Bacillus) 3 times daily for 1 month, dose not stated.
Treatment group (C)
30 mL to 60 mL lactulose plus probiotics daily for 1 month.
Outcomes 1. Venous ammonia level.

3. Minimal hepatic encephalopathy recovery.
Notes Additional information provided by the author. Contacted Professor BC Sharma on 14

October 2010
Sequence generation Low risk Participants were randomised according to

a computer-generated randomisation chart

Sharma 2008 (Continued)
Allocation concealment High risk Trial personnel were able to view the alloca-
tion sequence.
Blinding High risk The trial was not blinded.

Participants

Personnel

Outcome assessors
Incomplete outcome data High risk 13 participants in the control group and 5
All outcomes participants in the lactulose plus probiotic
group were lost to follow-up. Reasons are
unclear
Selective outcome reporting Low risk All outcomes reported in the methods (psy-
chometric tests outcomes, P300 auditory
event-related potential, venous ammonia
level, and Child-Pugh classification) were
measured and discussed on baseline and af-
ter 1 month. Personal communication with
the author revealed that no other outcomes
were assessed
Sharma 2014
Methods Design: a randomised parallel study

Treatment duration: Duration of the treatment was 2 months ± 3 days, or unless the
participant developed overt encephalopathy, expired, or was lost to follow up
Participants Setting: Department of Gastroenterology at a teaching hospital

Country: India
Age range (years): range unspecified, mean (SD): 39.1 (12.8)
Sex (M/F): 77/47
Stage/severity of hepatic encephalopathy: minimal hepatic encephalopathy by psychome-
tric tests (NCT A, FCT A, and DST) and critical flicker frequency (CFF); CTP A/B/
C: 35/52/37
Cause of hepatic encephalopathy: anti-HCV positive/HBsAg positive/history of ethanol:
17/30/34
Inclusions: A total of 317 cirrhotics were screened; 111 were excluded, and the remaining
206 cirrhotics were screened for MHE using NPTs or CFF test or both

Exclusions: The exclusion criteria included:

• People with overt HE or a history of overt HE in the past 6 weeks.
• History of alcohol intake during past 6 weeks.
• History of antibiotic or lactulose or probiotics use within the past 3 weeks.
• Gastrointestinal bleed in the past 6 weeks.
• History of recent use of drugs (< 6 weeks) affecting psychometric performance such
as antidepressants, antiepileptic, sedatives, psychotropic drugs.
• Spontaneous bacterial peritonitis or other infection in the past 7 days.
• Renal insufficiency with creatinine > 1.5 mg/dL.
• Electrolyte imbalance.
• Hepatocellular carcinoma.
• Significant comorbid illness, such as heart, respiratory, or renal failure; and any
neurological disease that could interfere with intellect or motor performance of the
person such as Alzheimer’s or Parkinson’s disease, respectively, or non-hepatic metabolic
encephalopathies.
• Previous transjugular intrahepatic portosystemic shunt or shunt surgery.
• People who restarted alcohol consumption during follow-up.
• Inability to do psychometric tests due to poor vision, or those having colour
blindness.
• People not having a fair knowledge of numbers and not having been to school for
at least 2 years.
• Women who were pregnant.
Interventions After the diagnosis of MHE was made, the participants were randomised into 4 groups:
DRUG 1 (l-ornithine l-aspartate (LOLA), 2 sachets 3 g each thrice a day) n = 31, DRUG
2 (tab rifaximin 400 mg thrice a day) n = 31, DRUG 3 (cap Velgut (5 billion CFUs of
Bifidobacterium breve, Bifidobacterium longum, Bifidobacterium infantis, Lactobacillus aci-
dophilus, Lactobacillus plantarum, Lactobacillus casei, Lactobacillus rhamnosus, Streptococcus
thermophilus, Saccharomyces boulardii)1 capsule twice a day) n = 32, and DRUG 4 (placebo
twice a day) n = 30
Outcomes 1. Death.
2. Recovery from MHE.
3. Overt HE.
4. CFF.
Notes Contacted Dr K Sharma on 14 March 2015, received no response

Funding source: “Source of Support: Nil, Conflict of Interest: None declared”. This study
declared the funding source and was deemed to be independently funded
Sequence generation Low risk “the block randomization method was uti-
lized for random allocation of drugs.”

Allocation concealment Low risk “The sequence remained concealed from the
investigator and the generator of the ran-
dom blocks did not participate in screening,
enrolment, or drug delivery.”
Blinding High risk The study was not blinded.

Participants

Personnel

Outcome assessors
Incomplete outcome data Unclear risk A total of 20 participants could not be fol-
All outcomes lowed up to the end of the study: 10 were
lost to follow-up, 6 went into overt HE, and
4 expired. Of the total 10 participants lost
to follow-up, the most were in the LOLA
group (4 cases) followed by the placebo
group (3 cases). The largest number of dete-
riorations in clinical state, i.e. development
of overt HE, occurred in the placebo group
(3 cases). Of the total 4 deaths, 2 were in
the placebo group and 1 each was in the ri-
faximin and Velgut groups. There were no
deaths in the LOLA group
Selective outcome reporting Unclear risk “Maximal number of deteriorations in clin-

ical state, that is, development of overt HE
among patients occurred in the placebo (3
cases) group.”
Overt HE development was not well re-
ported.
Funding source Low risk “Source of Support: Nil, Conflict of Inter-

est: None declared.”
Shavakhi 2014
Methods Design: randomised parallel trial + non-randomised cohort study

Participants Setting: The study was conducted on adults with MHE referred consecutively to the
gastroenterology clinic of a university hospital in Isfahan city (Iran) between June and
October 2012
Country: Iran

Shavakhi 2014 (Continued)
Age range (years): range not given, mean age (SD) 38.4 (9.6) years
Total numbers randomised: total (Gp-LPr/Gp-L): 46 (23/23)
Sex (M/F): 48/12
Stage/severity of hepatic encephalopathy: minimal hepatic encephalopathy; Child-Pugh
score A/B/C: 8/37/14 (data missing for 1 participant)
Cause of hepatic encephalopathy: viral/autoimmune/other: 44/11/5
Inclusions: The study was conducted on adults with MHE referred consecutively to the
gastroenterology clinic of a university hospital in Isfahan city (Iran) between June and
October 2012. Cirrhosis was diagnosed histologically (unless biopsy was contraindicated)
and on clinical and radiological grounds. Diagnosis of MHE was based on the Conn’s
modification of the Parsons-Smith classification (grade 1 and above)
Exclusions: People with overt HE, known brain lesions, active gastrointestinal bleeding,
active ongoing infection, renal impairment (serum creatinine > 2 mg/dL), electrolyte
abnormalities (serum sodium < 130 or > 150 meq/dL, serum potassium < 3.0 or > 5.5
meq/dL), and those who had received HE treatments such as lactulose and antibiotics or
consumed benzodiazepines, narcotics, opioids, or alcohol in the preceding 8 weeks were
not included in the trial
Interventions Participants were randomised into 2 groups: lactulose + probiotic (Gp-LPr) and lactulose
+ placebo (Gp-L). Another non-randomised group of participants who received probiotic
alone (Gp-Pr) were included separately for further comparisons; this group received neither
placebo nor lactulose.
All participants received routine treatment for cirrhosis, including diuretics, β-blockers,
endoscopic treatment, and a salt-restricted diet but not protein-restricted diet in those
with ascites. For Gp-LPr and Gp-L, lactulose syrup was administered as 30 to 60 mL/day
in divided doses for a stool frequency of 2 to 3 soft defecations per day. For Gp-LPr and
Gp-Pr, a multistrain probiotics compound, Balance (Protexin Co., Somerset, UK), was
administered twice daily after meal. Balance capsules contain 7 bacteria species including
Lactobacillus strains (L casei, L rhamnosus, L acidophilus, and L bulgaricus), Bifidobacterium
strains (B breve and B longum), and Streptococcus thermophilus. Total viable count is 1 × 108
CFU per capsule. Other ingredients are fructo-oligosaccharides as prebiotic, magnesium
stearate, and hydroxypropyl methyl cellulose. These interventions were continued for 14
consecutive days, and compliance was assessed with pill and bottle count
Outcomes Primary endpoint was improvement in MHE status, which was assessed by applying the
PHES at baseline, 14 days after start of the intervention (14th day), and then at 8 weeks’
follow-up (10th week). The PHES is a set of neuropsychological tests including the Line-
Tracing Test, Digit Symbol Test, Serial Dotting Test, and Number Connection Test.
These tests are used in the diagnosis and grading of MHE and examine visual perception,
visuospatial orientation, visual construction, motor speed and accuracy, concentration,
attention, and memory. Participants could achieve between +6 and −18 points.
Secondary outcomes were development of overt HE, admission to hospital for any other
complication of cirrhosis, or death
Notes The study was also registered at Iranian Registry of Clinical Trials
(IRCT201211012417N9)
Contacted Dr A Shavakhi on 14 March 2015, received no response
Funding source: “Source of Support: Isfahan University of Medical Sciences, Potential

Shavakhi 2014 (Continued)
competing interests: None declared”. This study declared the funding source and was
deemed to be independently funded
Sequence generation Low risk “Using a table of random numbers gener-

ated by random allocation software, patients
were randomized into two groups”
Blinding High risk “Because we could not provide an ap-

Participants propriate placebo for lactulose, our study
was not completely randomized and double
blinded, which could affect our results.”
Blinding High risk “Because we could not provide an ap-

Personnel propriate placebo for lactulose, our study
was not completely randomized and double
blinded, which could affect our results.”
Blinding Unclear risk Although the trial was not blinded, the ob-
Outcome assessors jective nature of the tests for MHE would
likely limit the effect of bias on MHE re-
covery outcomes
Incomplete outcome data Low risk “After randomization, two patients from the
All outcomes Gp-L, four patients from the Gp-LPr, and
three patients from the Gp-Pr declined to
receive intervention. Finally, 60 adult pa-
tients with cirrhosis (80% male, mean age
38.4 ± 9.6 years) started the trial and com-
pleted the intervention.”
“During the follow-up period, one patient
from each of the Gp-LPr and Gp-L was lost
to follow-up.”
Selective outcome reporting Unclear risk The outcomes to be measured were not
clearly specified in trial as registered at Ira-
nian Registry of Clinical Trials (trial num-
ber IRCT201211012417N9)
Funding source Low risk “Source of Support: Isfahan University of

Medical Sciences, Potential competing in-
terests: None declared.”

Vlachogiannakos 2014
Methods Design: a randomised parallel trial


Country: Greece
Age range (years): range unspecified, mean (SD): 59 (10)
Sex (M/F): 62/10
Stage/severity of hepatic encephalopathy: minimal hepatic encephalopathy; “Mean (SD)
Child-Pugh score: 6.4 (1.6), 46% Child-Pugh A, mean (SD) MELD score: 11.9 (3.6)”
Cause of hepatic encephalopathy: 58% alcoholic cirrhosis
Inclusions: “In a period of 18 months, we screened 142 consecutive patients without overt
HE for MHE using both, psychometric (number connection test, NCT) and neurophys-
iological (brainstem auditory evoked potentials, BAEP) modalities.”
Exclusions: unclear from abstract
Interventions 72 participants were equally randomised into Lactobacillus plantarum 299v at a dose of
1010 units per sachet (Lp299v) or identical placebo, given twice a day for a period of 12
weeks
Outcomes 1. Development of overt HE.

2. Adherence to treatment.
3. MHE reversal.
4. Psychometric test score (NCT, BAEP).
5. Serum fasting ammonia.
Notes Contaced Dr J Vlachogiannakos on 22 December 2014, received no response

Funding source: abstract only, unable to assess
Blinding Low risk “identical placebo” used

Participants

Personnel

Outcome assessors

Vlachogiannakos 2014 (Continued)

All outcomes
Zhao 2013

Trial duration: 1 month
Participants Setting: hospital gastroenterology clinic

Country: China
Age range (years): range unspecified, mean (SD): control group 41.15 (11.85), lactulose
group 43.85 (11.10), probiotic group 44.25 (11.85)
Sex (M/F): 92/28
Language: Chinese language/s, with psychometric testing language adjusted to suit pop-
ulation
Stage/severity of hepatic encephalopathy: minimal hepatic encephalopathy; CTP A/B/C:
50/39/31
Cause of hepatic encephalopathy: chronic hepatitis B
Inclusions:
• Compliance with chronic hepatitis B prevention and treatment guidelines.
• Diagnosed with MHE based on psychometric testing.
Exclusions:
• Clinical symptoms of HE.
• Clinical symptoms of HE in last 6 weeks.
• History of upper GI bleeding in the last 6 weeks.
• Active infection.
• Renal impairment and creatinine greater than 133 µM/L.
• Electrolyte abnormality (Na+ < 130 mM/L or > 150 mM/L; K+ < 3 mM/L or > 5.5
mM/L).
• People with alcoholic cirrhosis.
• Recently taking antibiotics, probiotics, or aspartate/ornithine.
• Took psychotropic drugs in the last 6 weeks.
• TIPS shunt.
• Surgery.
• Liver tumours.
• Serious systemic disease such as heart failure, pulmonary disease, neurological and
psychiatric illness.
• Visual impairment.
• Impairment on intelligence tests.

Zhao 2013 (Continued)
Interventions Standard treatment of liver cirrhosis (control) compared to both lactulose (twice daily, 30
to 60 mL with soft stools 2 to 3 times daily) and probiotic (110 million CFU twice daily
for 1 month) groups
Outcomes 1. All-cause mortality.

2. MHE improvement.
3. Arterial ammonia level.
4. Adverse effects.
5. Change of/withdrawal from treatment.
Notes We found no contact details.

Sequence generation Low risk Randomised table used.
Blinding Unclear risk Unclear from study

Participants

Personnel

Outcome assessors
Incomplete outcome data Unclear risk Unclear from study

All outcomes
Funding source Unclear risk Unclear from study
Zhitai 2013
Methods Design: unclear from abstract

Trial duration: unclear from abstract
Treatment duration: unclear from abstract
Participants Setting: unclear from abstract

Country: China
Age range (years): unclear from abstract
Sex (M/F): unclear from abstract
Zhitai 2013 (Continued)
Language: unclear from abstract

Stage/severity of hepatic encephalopathy: hepatic encephalopathy (excluding clinical IV
stage)
Cause of hepatic encephalopathy: unclear from abstract
Inclusions: unclear from abstract
Exclusions: unclear from abstract
Interventions Treatment group: routine liver protection against hepatic coma therapy, oral or nasal
feeding of live Bacillus cereus capsules
Control group: conventional liver protection against hepatic coma therapy, oral or nasal
feeding of lactulose
Outcomes 1. Resolution of hepatic encephalopathy.

2. Blood ammonia levels.
Notes We found no contact details.

Funding source: abstract only, unable to assess

Participants

Personnel

Outcome assessors

All outcomes

Ziada 2013
Methods Design: randomised parallel trial

Trial duration: 1 month
Participants Setting: outpatient clinic and inpatient wards

Country: Egypt
Age range (years): range unclear, group A/B /C mean (SD): 48.8 (8.2)/50.3 (7.8)/51.2 (7.
5)
Sex (M/F): 55/20 (excluding attrition)
Stage/severity of hepatic encephalopathy: minimal hepatic encephalopathy screened by
NCT-A, DST, and SDT; Child A/B/C: 8/41/26
Cause of hepatic encephalopathy: unspecified
Inclusions: All cirrhotic patients attending the Tropical Medicine and Infectious Disease
outpatient clinic and inpatient wards from March 2010 to January 2012 were encouraged
to join this prospective randomised trial
Exclusions: The exclusion criteria were the presence of overt HE, alcohol intake, gas-
trointestinal haemorrhage or spontaneous bacterial peritonitis during the past 6 weeks,
previous shunt surgery and associated heart, respiratory, or renal failure as well as history
of any neurologic or metabolic encephalopathies. People on psychoactive drugs such as
antidepressants or sedatives were excluded
Interventions Group A received lactulose (30 to 60 mL/day); group B received a probiotic (1 capsule
containing 106 Lactobacillus acidophilus 3 times/day); and group C was the control.
Outcomes 1. Psychometric tests (normalisation, persistence of abnormality in 1 psychometric

test, no improvement).
2. Gut microecology study.
3. Ammonia level.
4. Brain metabolites using MRS.
Notes Contacted Dr DH Ziada on 14 March 2015, received no response

Sequence generation Unclear risk “Patients were allocated by simple randomi-

sation to three parallel equal groups of 30
patients each.”
Blinding High risk “This study was designed as overtime open-

Participants label randomised controlled trial testing the
role of a probiotic in comparison with lac-
tulose or no therapy in MHE patients.”

Ziada 2013 (Continued)
Blinding High risk “This study was designed as overtime open-

Personnel label randomised controlled trial testing the
role of a probiotic in comparison with lac-
tulose or no therapy in MHE patients.”
Blinding Low risk Although the trial was not blinded, the ob-
Outcome assessors jective nature of the tests for MHE would
likely limit the effect of bias on MHE re-
covery outcomes
Incomplete outcome data Low risk Group A: 30 allocated to lactulose, 30 re-

All outcomes ceived lactulose, 2 lost to follow-up, 2 dis-
continued therapy, 2 overt encephalopathy,
24 participants analysed
Group B: 30 allocated to probiotics, 30 re-
ceived probiotics, 2 lost to follow-up, 1 dis-
continued therapy, 1 overt encephalopathy,
26 participants analysed
Group C: 30 allocated, 0 lost to follow-up,
5 overt encephalopathy, 25 analysed
Selective outcome reporting Unclear risk Unable to assess
Funding source Unclear risk “The authors declared that there is no con-
flict of interest”
ALT = alanine aminotransferase; BAEP = brainstem auditory evoked potentials; CFF = critical flicker frequency; CFU = colony forming
unit; CNS = central nervous system; CT = computed tomography; CTP = Child-Turcotte-Pugh; DST = digit symbol test; FCT =
figure connection test; GI = gastrointestinal; HBV = hepatitis B virus; HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus;
HE = hepatic encephalopathy; HRQOL = health-related quality of life; IL-6 = interleukin 6; LOLA = L-ornithine-L-aspartate; MCS
= Mental Component summary; MELD = Model for End-Stage Liver Disease; MHE = minimal hepatic encephalopathy; MRS =
Magnetic resonance spectroscopy; NASH = non-alcoholic steatohepatitis;
NCT = Number Connection Test; NIH = National Institutes of Health; NPT = neuropsychological testing; OCTT = orocaecal transit
time;
OHE = overt hepatic encephalopathy; PHES = psychometric hepatic encephalopathy score; QOL= quality of life; SD = standard
deviation; SDT = serial dotting test; SF-36 = 36-Item Short Form Health Survey; SIBO = small intestinal bacterial overgrowth; TIPS
= transjugular intrahepatic portosystemic shunt; TNF alpha = tumour necrosis factor-alpha; USG = ultrasonography

Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Adams 2006 No hepatic encephalopathy patients involved
Agrawal 2012 Not a randomised trial
Agrawal 2012a Hepatic encephalopathy not used as participant selection criteria
Al 2009 Not a randomised trial
Albillos 2002 No hepatic encephalopathy patients involved
Alisi 2014 No hepatic encephalopathy patients involved
Aller 2011 No hepatic encephalopathy patients involved
Almeida 2006 Not a randomised trial
Arya 2010 Not a randomised trial
Bai 2013 Not a randomised trial
Bajaj 2008a Not a randomised trial
Bajaj 2008b Not a randomised trial
Bajaj 2014 Not a randomised trial
Barclay 2011 Not a randomised trial
Barreto-Zuniga 2001 No hepatic encephalopathy patients involved
Bass 2007 Not a randomised trial
Bengmark 2009a Not a randomised trial
Bengmark 2011 Not a randomised trial
Bengmark 2013 Not a randomised trial
Bismuth 2011 Not a randomised trial
Boca 2004 Not a randomised trial
Bongaerts 2005 Not a randomised trial
Cabre 2005 Not a randomised trial

(Continued)
Cash 2010 Not a randomised trial
Chadalavada 2010 Not a randomised trial
Chauhan 2012 Not a randomised trial
Cheung 2012 Not a randomised trial
Chikhacheva 2014 Not a randomised trial
Ciorba 2012 Not a randomised trial
Colle 1989 Hepatic encephalopathy not confirmed
Conn 1970 Not a randomised trial
Crittenden 2013 Not a randomised trial
Dai 2014 No probiotic used
Dasarathy 2003 No probiotic used
Dbouk 2006 Not a randomised trial
De Micco 2012 Not a randomised trial
Demeter 2006 Not a randomised trial
Dhiman 2004 Not a randomised trial
Dhiman 2012 Hepatic encephalopathy not used as participant selection criteria
Dhiman 2014 Hepatic encephalopathy not used as participant selection criteria
Ding 2014 Not a randomised trial
Ding 2014a Not a randomised trial
Doron 2005 Not a randomised trial

(Continued)
Druart 2014 Not a randomised trial
Dylag 2014 Not a randomised trial
EASL 2012 Not a randomised trial
Eguchi 2011 Not probiotic
El-Nezami 2006 No hepatic encephalopathy patients involved
Eslamparast 2014 No hepatic encephalopathy patients involved
Fan 2009 No hepatic encephalopathy patients involved
Fan 2013 Not a randomised trial
Fehervari 2012 Not a randomised trial
Ferenci 2001 Not a randomised trial
Ferenci 2007 Not a randomised trial
Feret 2010 Not probiotic
Ferreira 2010 Not a randomised trial
Festi 2014 Not a randomised trial
Finney 2007 No probiotics used
Floch 2015 Not a randomised trial
Fontana 2013 Not a randomised trial
Fooladi 2013 Not a randomised trial
Foster 2010 Not a randomised trial
Fujita 2008 No hepatic encephalopathy patients involved
Fuster 2007 Not a randomised trial
Galhenage 2006 Not a randomised trial
Ganguli 2013 No hepatic encephalopathy patients involved
Garcia 2012 Not a randomised trial
Garcovich 2012 Not a randomised trial

(Continued)
Gareau 2014 Not a randomised trial
Gluud 2013 Not a randomised trial
Gomez-Hurtado 2014 Not a randomised trial
Grat 2014 Not a randomised trial
Gratz 2010 Not a randomised trial
Greco 2007 Groups non-comparable
Gu 2014 No hepatic encephalopathy patients involved
Guarner 2009 Not a randomised trial
Guarner 2012 Not a randomised trial
Guerrero 2008 Not a randomised trial
Gupta 2010 No hepatic encephalopathy patients involved
Gupta 2010a No hepatic encephalopathy patients involved
Gupta 2013 No hepatic encephalopathy patients involved
Hellinger 2002 No probiotic used
Higashikawa 2010 No hepatic encephalopathy patients involved
Holte 2012 Not a randomised trial
Hotten 2003 No hepatic encephalopathy patients involved
Hutt 2011 Not a randomised trial
Ianiro 2014 Not a randomised trial
Iannitti 2010 Not a randomised trial
Imler 1971 Not a randomised trial
Ivanovic 2015 Not a randomised trial
Janczyk 2012 Not a randomised trial
Jayakumar 2012 No hepatic encephalopathy patients involved
Jayakumar 2013 No hepatic encephalopathy patients involved

(Continued)
Jeejeebhoy 2004 Not a randomised trial
Jiang 2008 No probiotics used
Jones 2013 No hepatic encephalopathy patients involved
Jonkers 2007 Not a randomised trial
Jover-Cobos 2014 Not a randomised trial
Jun 2013 No hepatic encephalopathy patients involved
Jurado 2012 Not a randomised trial
Kachaamy 2011 Not a randomised trial
Kadayifci 2007 Not a randomised trial
Karczewski 2010 No hepatic encephalopathy patients involved
Keeffe 2007 Not a randomised trial
Khungar 2012 Not a randomised trial
Kirpich 2008 No hepatic encephalopathy patients involved
Kitagawa 2015 Not a randomised trial
Koga 2013 No hepatic encephalopathy patients involved
Kremer 1974 Not a randomised trial
Kumashiro 2008 Not a randomised trial
Kwak 2014 No hepatic encephalopathy patients involved
Lata 2006 No hepatic encephalopathy patients involved
Lata 2007a No hepatic encephalopathy patients involved
Lata 2011 Not a randomised trial
Leber 2012 Not a randomised trial

(Continued)
Liboredo 2015 Not a randomised trial
Lien 2015 No hepatic encephalopathy patients involved
Lighthouse 2004 No hepatic encephalopathy patients involved
Liu 2006 Not available
Liu 2009 Not available
Liu 2010 Not a randomised trial
Liu 2012 Not a randomised trial
Llorente 2015 Not a randomised trial
Loguercio 2002 No hepatic encephalopathy patients involved
Loguercio 2005 No hepatic encephalopathy patients involved
Louvet 2015 Not a randomised trial
Lu 2011 Not a randomised trial
Luna 2010 Hepatic encephalopathy not used as patient selection criteria
Lunia 2012 Hepatic encephalopathy not used as patient selection criteria
Lunia 2014a Hepatic encephalopathy not used as patient selection criteria
Luo 2011 Not a randomised trial
Ma 2013 Not a randomised trial
Machado 2012 Not a randomised trial
Madsen 2008 No hepatic encephalopathy patients involved
Malaguarnera 2007 Not a probiotic alone
Malaguarnera 2012 No hepatic encephalopathy patients involved
Marteau 2001 Not a randomised trial
Marteau 2002 Not a randomised trial
Marteu 2001 Not a randomised trial
Michelfelder 2010 Not a randomised trial

(Continued)
Minemura 2015 Not a randomised trial
Mishra 2012 Not a randomised trial
Mohammad 2012 Not a randomised trial
Montagnese 2012 Not a randomised trial
Montgomery 2011 Not a randomised trial
Montrose 2005 Not a randomised trial
Moreno-Luna 2011 Not a randomised trial
Morgan 2007 Not a randomised trial
Mullen 2007 Not a randomised trial
Nabavi 2014 No hepatic encephalopathy patients involved
Nazir 2010 Prophylaxis, not treatment
NCT01135628 Not a randomised trial
Olveira 2007 Not a randomised trial
Oshea 2010 Not a randomised trial
Pande 2009 No hepatic encephalopathy patients involved
Pande 2012 No hepatic encephalopathy patients involved
Paolella 2014 Not a randomised trial
Park 2007 Not a randomised trial
Patel 2015 Not a randomised trial
Pawar 2012 Hepatic encephalopathy not used as participant selection criteria
Phongsamran 2010 Not a randomised trial
Plaza-Diaz 2014 No hepatic encephalopathy patients involved
Poh 2012 Not a randomised trial
Poustchi 2013 No hepatic encephalopathy patients involved
Prakash 2013 Not a randomised trial

(Continued)
Quigley 2006 Not a randomised trial
Quigley 2014a Not a randomised trial
Rahimi 2012 Not a randomised trial
Rahimi 2013 Not a randomised trial
Rayes 2001 No hepatic encephalopathy patients involved
Read 1966 Not a randomised trial
Reddy 2013 Not a randomised trial
Rifatbegovic 2010 No hepatic encephalopathy patients involved
Riggio 2009 Not a randomised trial
Rincon 2014 Not a randomised trial
Riordan 2007 No hepatic encephalopathy patients involved
Riordan 2010 No probiotic used
Rivkin 2011 Not a randomised trial
Romero-Gomez 2010 Not a randomised trial
Sanchez 2015 No hepatic encephalopathy patients involved
Scevola 1989 No probiotics used
Schiano 2010 Not a randomised trial
Schuster-Wolff-Bühring 2010a Not a randomised trial
Schuster-Wolff-Bühring 2010b Not a randomised trial

(Continued)
Segura-Ortega 2010 No hepatic encephalopathy patients involved
Shang 2013 No hepatic encephalopathy patients involved
Sharma 2010 Not a randomised trial
Sharma 2012 No probiotic used
Sharma 2014a Hepatic encephalopathy not used as participant selection criteria
Sharma 2014b Not a randomised trial
Shawcross 2005 Not a randomised trial
Shen 2013 Not available
Shen 2014 Not available
Sheth 2008 Not a randomised trial
Shu 2008 Not available
Shukla 2009 Not a randomised trial
Shukla 2010a Not a randomised trial
Solga 2003 Not a randomised trial
Soriano 2013 Not a randomised trial
Soriano 2013a Not a randomised trial
Stadlbauer 2008 No hepatic encephalopathy patients involved
Stewart 2007 Not a randomised trial
Strasser 2011 Not a randomised trial
Suk 2012 No hepatic encephalopathy patients involved
Sundaram 2009 Not a randomised trial

(Continued)
Tang 2011 Not a randomised trial
Tapper 2015 Not a randomised trial
Tarantino 2015 Not a randomised trial
Tarao 1995 No probiotics used
Tojo 2014 Not a randomised trial
Toris 2011 Not a randomised trial
Tsochatzis 2012 Not a randomised trial
Tsochatzis 2014 Not a randomised trial
Upadhyay 2012 Not a randomised trial
Usami 2011 No hepatic encephalopathy patients involved
Valentini 2015 No hepatic encephalopathy patients involved
Videhult 2015 No hepatic encephalopathy patients involved
Vilstrup 2014 Not a randomised trial
Vilstrup 2014a Not a randomised trial
Vyas 2012 Not a randomised trial
Waghray 2014 Not a randomised trial
Waghray 2015 Not a randomised trial
Wang 2012 Not available
Wang 2015 Not available
Welliver 2012 Not a randomised trial
Wong 2013a No hepatic encephalopathy patients involved
Woo 2012 Not a randomised trial
Wright 2007 Not a randomised trial
Wu 2008 Not a randomised trial

(Continued)
Xu 2012 Not a randomised trial
Xu 2014 Not a randomised trial
Xu 2014a Not a randomised trial
Yakabe 2009 No hepatic encephalopathy patients involved
Yao 2014 Not a randomised trial
Yasutake 2012 Not a randomised trial
Zafirova 2010 Not a randomised trial
Zamberlin 2012 Not a randomised trial
Zhang 2014 Not a randomised trial
Zhao 2004 No hepatic encephalopathy patients involved
Zucker 2014 Not a randomised trial
Characteristics of studies awaiting assessment [ordered by study ID]
ACTRN12610001021066

Participants Country: Australia

Age range (years):
Total numbers randomised: 80 target sample size
Inclusions: Child’s B or C cirrhosis on lactulose aged between 18 and 70 years who are abstinent from alcohol and
illegal drugs for at least 6 months. If on methadone, must be dose stable for > 6 months
Exclusions:
• Pregnancy.
• < 18 years.
• > 70 years.
• Current alcohol use.
• Current intravenous drug use.
• Sepsis.
• Grade 4 encephalopathy.
Interventions 1. Synbiotics + branched-chain amino acids (BCAAs).

2. BCAAs + placebo for synbiotics.
3. Placebo for BCAAs + placebo for synbiotics.
Synbiotic 2000 Forte is packaged in 10-gram single-dose sachets containing the following: Natural and digestible

ACTRN12610001021066 (Continued)
fibres: * 2.5 g oat bran; * 2.5 g pectin; * 2.5 g resistant starch; * 2.5 g inulin. Probiotic bacteria: * Lactobacillus paracasei
ssp paracasei 10 x 10¹¹; * Lactobacillus plantarum 10 x 10¹¹; * Leuconostoc mesenteroides 10 x 10¹¹; * Pediococcus
pentosaceus 10 x 10¹¹ (Medipharm). Dose is 1 sachet/day mixed with juice, jam, or honey according to participant’s
tolerance. Duration of supplementation is 56 days
Branched-chain amino acid preparation is HepatAmine (Nutricia), which is a mixture of branched-chain amino acids
+ sugars. Dose is 1 sachet at night mixed with 200 mL lemonade or fruit juice. Duration of supplementation is 56
days
Placebo for synbiotics is 10 g crystalline starch packaged similarly to Synbiotic 2000 Forte. Dose is 1 sachet/day
mixed with juice, jam, or honey according to participant’s tolerance. Duration of supplementation is 56 days. Placebo
for BCAAs is 29 g glucose + 15 g Vitafresh. Dose is 1 sachet at night mixed with 200 mL lemonade or fruit juice.
Duration of supplementation is 56 days
Outcomes Primary outcome:

1. Effects of supplementation with synbiotics and/or BCAAs on levels of hepatic encephalopathy (Trail Making
Tests A and B and the Inhibitory Control Test).
Secondary outcomes:
1. Effects of synbiotics or BCAAs or both on quality of life outcomes measured by liver disease short form quality
of life (SFLDQOL) questionnaire and depression and anxiety score (DASS).
2. Effects of supplementation with synbiotics or BCAAs or both on frequency of hospitalisation.
3. Effects of supplementation with synbiotics or BCAAs or both on severity of the participant’s chronic liver
disease using the Child-Pugh Score and Model for End-Stage Liver Disease (MELD).
4. Effects of supplementation with synbiotics or BCAAs or both on body composition and hand grip strength.
(Body composition is assessed by anthropometry, measurements of midarm circumference and triceps skinfold and
calculated midarm muscle circumference. Hand grip strength is measured using a dynamometer.)
5. Effects of supplementation with synbiotics or BCAAs or both on appetite and oral intake. (Appetite is a
subjective assessment by the participant using a visual analogue scale. Oral intake is assessed using a 3-day food
history recorded by the participant at each time point).
Notes Data obtained from trial registry www.anzctr.org.au/, trial ID: ACTRN12610001021066.
IRCT201211012417N9

Trial duration: 14 days
Participants Country: Iran

Age range: between 18 to 65 years
Total number randomised: target sample size 40
Inclusion criteria:
• Age between 18 to 65 years.
• Diagnosis of hepatic encephalopathy.
• Filling consent form.
Exclusion criteria:
• Refusal to fill consent form.
• Active gastrointestinal bleeding.
• Alcohol usage.
• Active infection.

IRCT201211012417N9 (Continued)
• Lactolos or antibiotic therapy within the previous 2 weeks.

• Space-occupying lesion in central nervous system.
Interventions Intervention 1: probiotic capsule (Protexin).

Intervention 2: placebo capsule.
Outcomes Consiousness level. (Time point: beginning and 14 days postintervention. Method of measurement: questionnaire.)
Notes Data obtained from apps.who.int/trialsearch/Trial2.aspx?TrialID=IRCT201211012417N9.
NCT01798329

Participants Country: Italy

Total numbers randomised: target sample size 50
Inclusion criteria:
• Extra-hepatic portal vein thrombosis.
• Age between 4 and 20 years.
• Knowledge of Italian language.
• Absence of perceptive or communicative deficit.
• Absence of psychiatric disease or mental retardation.
Exclusion criteria:
• Medical contraindications for required evaluations.
• Infective pathologies.
• Parenchymal hepatic pathologies.
Interventions Dietary supplement: probiotic VSL#3
Outcomes Primary outcome

1. Neuropsychological and electrophysiological aspects [Time Frame: after 15 weeks of probiotic or placebo
treatment].
Secondary outcomes
1. Abdomen scan with colour Doppler technique [Time Frame: after 15 weeks of probiotic or placebo treatment].
2. Biochemical blood test [Time Frame: after 15 weeks of probiotic or placebo treatment].
3. Bowel frequency and characteristics [Time Frame: after 15 weeks of probiotic or placebo treatment].
4. Dietary anamnesis (last 3 days) [Time Frame: after 15 weeks of probiotic or placebo treatment].
5. Neurological evaluation [Time Frame: after 15 weeks of probiotic or placebo treatment].
6. Urine and faeces analysis [Time Frame: after 15 weeks of probiotic or placebo treatment].
Notes Data obtained from apps.who.int/trialsearch/Trial2.aspx?TrialID=NCT01798329.

DATA AND ANALYSES
Comparison 1. Probiotic versus placebo or no intervention
No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size
1 All-cause mortality 7 404 Risk Ratio (M-H, Random, 95% CI) 0.58 [0.23, 1.44]
1.1 2 weeks 1 46 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
1.2 1 month 1 80 Risk Ratio (M-H, Random, 95% CI) 0.33 [0.01, 7.95]
1.3 2 months 3 117 Risk Ratio (M-H, Random, 95% CI) 0.72 [0.11, 4.66]
2 No recovery (incomplete 10 574 Risk Ratio (M-H, Random, 95% CI) 0.67 [0.56, 0.79]
resolution of clinical
symptoms)
3 Adverse events 11 Risk Ratio (M-H, Random, 95% CI) Subtotals only
3.1 Overt hepatic 10 585 Risk Ratio (M-H, Random, 95% CI) 0.29 [0.16, 0.51]
encephalopathy
3.2 Infection 1 37 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
3.3 Hospitalisation 3 163 Risk Ratio (M-H, Random, 95% CI) 0.67 [0.11, 4.00]
3.4 Intolerance leading to 1 37 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
discontinuation
3.5 Change of/or withdrawal 9 551 Risk Ratio (M-H, Random, 95% CI) 0.70 [0.46, 1.07]
from treatment
4 Quality of life 3 Mean Difference (IV, Random, 95% CI) Subtotals only
4.1 SF-36 Physical 1 20 Mean Difference (IV, Random, 95% CI) 0.0 [-5.47, 5.47]
4.2 SF-36 Mental 1 20 Mean Difference (IV, Random, 95% CI) -4.0 [-9.82, 1.82]
4.3 Change in Total SIP Score 2 95 Mean Difference (IV, Random, 95% CI) -3.66 [-7.75, 0.44]
4.4 Change in SIP 2 95 Mean Difference (IV, Random, 95% CI) -3.54 [-4.95, -2.12]
Psychological Score
4.5 Change in SIP Physical 2 95 Mean Difference (IV, Random, 95% CI) -2.94 [-4.44, -1.44]
Score
5 Plasma ammonia concentration 10 705 Mean Difference (IV, Random, 95% CI) -8.29 [-13.17, -3.41]
(final and change scores)
(µmol/L)
5.1 1 month 5 357 Mean Difference (IV, Random, 95% CI) -5.55 [-10.67, -0.42]
5.2 2 months 4 211 Mean Difference (IV, Random, 95% CI) -5.11 [-14.56, 4.34]
5.3 3 months 1 73 Mean Difference (IV, Random, 95% CI) -6.79 [-10.39, -3.19]
5.4 6 months 1 64 Mean Difference (IV, Random, 95% CI) -31.08 [-40.50, -21.
66]

Comparison 2. Probiotic versus lactulose
No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size
1 All-cause mortality 2 200 Risk Ratio (M-H, Random, 95% CI) 5.00 [0.25, 102.00]
2 No recovery (incomplete 7 430 Risk Ratio (M-H, Random, 95% CI) 1.01 [0.85, 1.21]
resolution of clinical
symptoms)
2.1 1 month or less 5 255 Risk Ratio (M-H, Random, 95% CI) 0.94 [0.75, 1.20]
3 Adverse events 7 Risk Ratio (M-H, Random, 95% CI) Subtotals only
3.1 Overt hepatic 6 420 Risk Ratio (M-H, Random, 95% CI) 1.17 [0.63, 2.17]
encephalopathy
3.2 Infection 0 0 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
3.3 Hospitalisation 1 80 Risk Ratio (M-H, Random, 95% CI) 0.33 [0.04, 3.07]
3.4 Intolerance leading to 3 220 Risk Ratio (M-H, Random, 95% CI) 0.35 [0.08, 1.43]
discontinuation
3.5 Change of/or withdrawal 7 490 Risk Ratio (M-H, Random, 95% CI) 1.27 [0.88, 1.82]
from treatment
4 Health-related quality of life 1 Mean Difference (IV, Random, 95% CI) Subtotals only
4.1 Change in Total SIP Score 1 69 Mean Difference (IV, Random, 95% CI) 0.65 [-1.13, 2.43]
4.2 Change in SIP 1 69 Mean Difference (IV, Random, 95% CI) 0.48 [-1.04, 2.00]
Psychological Score
4.3 Change in SIP Physical 1 69 Mean Difference (IV, Random, 95% CI) 0.38 [-0.61, 1.37]
Score
5 Plasma ammonia concentration 6 325 Mean Difference (IV, Random, 95% CI) -2.93 [-9.36, 3.50]
(final and change scores)
(µmol/L)
5.1 1 month or less 5 248 Mean Difference (IV, Random, 95% CI) -4.30 [-13.17, 4.56]
5.2 3 months 1 77 Mean Difference (IV, Random, 95% CI) 1.16 [-1.96, 4.28]

Analysis 1.1. Comparison 1 Probiotic versus placebo or no intervention, Outcome 1 All-cause mortality.
Review: Probiotics for people with hepatic encephalopathy
Comparison: 1 Probiotic versus placebo or no intervention
Outcome: 1 All-cause mortality
Study or subgroup Probiotic No intervention Risk Ratio Weight Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI CI
1 2 weeks
Shavakhi 2014 0/23 0/23 Not estimable
Subtotal (95% CI) 23 23 Not estimable

Total events: 0 (Probiotic), 0 (No intervention)
Heterogeneity: not applicable
Test for overall effect: not applicable
2 1 month
Zhao 2013 0/40 1/40 8.3 % 0.33 [ 0.01, 7.95 ]
Subtotal (95% CI) 40 40 8.3 % 0.33 [ 0.01, 7.95 ]

Test for overall effect: Z = 0.68 (P = 0.50)
3 2 months
Bajaj 2014a 0/14 0/16 Not estimable
Bajaj 2008 1/17 0/8 8.7 % 1.50 [ 0.07, 33.26 ]
Sharma 2014 1/32 2/30 15.2 % 0.47 [ 0.04, 4.91 ]
Subtotal (95% CI) 63 54 23.9 % 0.72 [ 0.11, 4.66 ]

Heterogeneity: Tau2 = 0.0; Chi2 = 0.34, df = 1 (P = 0.56); I2 =0.0%
4 3 months
Mittal 2009 0/40 1/40 8.3 % 0.33 [ 0.01, 7.95 ]
Lunia 2014 4/42 6/39 59.4 % 0.62 [ 0.19, 2.03 ]
Subtotal (95% CI) 82 79 67.7 % 0.57 [ 0.19, 1.74 ]

Total (95% CI) 208 196 100.0 % 0.58 [ 0.23, 1.44 ]
Test for subgroup differences: Chi2 = 0.17, df = 2 (P = 0.92), I2 =0.0%
0.005 0.1 1 10 200

Favours probiotic Favours control

Analysis 1.2. Comparison 1 Probiotic versus placebo or no intervention, Outcome 2 No recovery
(incomplete resolution of clinical symptoms).
Outcome: 2 No recovery (incomplete resolution of clinical symptoms)

M- M-
n/N n/N CI CI
1 1 month
Liu 2004 10/20 10/20 6.0 % 1.00 [ 0.54, 1.86 ]
Sharma 2008 13/30 14/31 6.9 % 0.96 [ 0.55, 1.69 ]
Ziada 2013 13/27 27/30 10.2 % 0.53 [ 0.36, 0.81 ]
Zhao 2013 24/36 30/34 15.0 % 0.76 [ 0.58, 0.98 ]
Subtotal (95% CI) 113 115 38.1 % 0.75 [ 0.58, 0.96 ]

Heterogeneity: Tau2 = 0.02; Chi2 = 4.19, df = 3 (P = 0.24); I2 =28%
2 2 months
Bajaj 2008 5/17 8/8 4.8 % 0.32 [ 0.16, 0.66 ]
Bajaj 2014a 10/14 12/16 9.5 % 0.95 [ 0.62, 1.47 ]
Sharma 2014 16/32 21/30 10.0 % 0.71 [ 0.47, 1.09 ]
Subtotal (95% CI) 63 54 24.3 % 0.65 [ 0.38, 1.10 ]

3 3 months
Vlachogiannakos 2014 14/35 30/33 9.9 % 0.44 [ 0.29, 0.67 ]
Lunia 2014 20/42 34/39 12.3 % 0.55 [ 0.39, 0.77 ]
Mittal 2009 26/40 36/40 15.4 % 0.72 [ 0.56, 0.93 ]
Subtotal (95% CI) 117 112 37.6 % 0.58 [ 0.43, 0.78 ]

Total (95% CI) 293 281 100.0 % 0.67 [ 0.56, 0.79 ]
Test for overall effect: Z = 4.49 (P < 0.00001)
0.1 0.2 0.5 1 2 5 10


Analysis 1.3. Comparison 1 Probiotic versus placebo or no intervention, Outcome 3 Adverse events.
Outcome: 3 Adverse events

M- M-
n/N n/N CI CI
1 Overt hepatic encephalopathy
Liu 2004 0/20 0/20 Not estimable
Shavakhi 2014 0/23 1/23 3.4 % 0.33 [ 0.01, 7.78 ]
Bajaj 2008 0/17 2/8 3.9 % 0.10 [ 0.01, 1.87 ]
Ziada 2013 1/30 5/30 7.8 % 0.20 [ 0.02, 1.61 ]
Mittal 2009 2/40 4/40 12.6 % 0.50 [ 0.10, 2.58 ]
Zhao 2013 2/40 7/40 14.8 % 0.29 [ 0.06, 1.29 ]
Qiao 2010 2/32 12/32 16.9 % 0.17 [ 0.04, 0.69 ]
Lunia 2014 5/42 11/39 36.4 % 0.42 [ 0.16, 1.11 ]
Subtotal (95% CI) 299 286 100.0 % 0.29 [ 0.16, 0.51 ]

2 Infection

3 Hospitalisation
Shavakhi 2014 1/23 1/23 43.1 % 1.00 [ 0.07, 15.04 ]
Mittal 2009 1/40 2/40 56.9 % 0.50 [ 0.05, 5.30 ]
Subtotal (95% CI) 81 82 100.0 % 0.67 [ 0.11, 4.00 ]

0.001 0.01 0.1 1 10 100 1000

(Continued . . . )

(. . .Continued)
M- M-
n/N n/N CI CI
4 Intolerance leading to discontinuation

5 Change of/or withdrawal from treatment
Bajaj 2008 3/17 0/8 2.1 % 3.50 [ 0.20, 60.70 ]
Shavakhi 2014 4/23 2/23 6.5 % 2.00 [ 0.41, 9.87 ]
Mittal 2009 3/40 3/40 7.0 % 1.00 [ 0.21, 4.66 ]
Bajaj 2014a 4/18 3/19 8.9 % 1.41 [ 0.36, 5.43 ]
Sharma 2008 5/35 4/35 10.5 % 1.25 [ 0.37, 4.27 ]
Ziada 2013 4/30 5/30 10.7 % 0.80 [ 0.24, 2.69 ]
Zhao 2013 6/40 13/40 19.2 % 0.46 [ 0.19, 1.09 ]
Lunia 2014 9/42 17/39 27.6 % 0.49 [ 0.25, 0.97 ]
Subtotal (95% CI) 282 269 100.0 % 0.70 [ 0.46, 1.07 ]

Test for subgroup differences: Chi2 = 6.14, df = 2 (P = 0.05), I2 =67%
0.001 0.01 0.1 1 10 100 1000


Analysis 1.4. Comparison 1 Probiotic versus placebo or no intervention, Outcome 4 Quality of life.
Outcome: 4 Quality of life
Mean Mean
Study or subgroup Probiotic No intervention Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI
1 SF-36 Physical
Bajaj 2008 14 -39 (5) 6 -39 (6) 100.0 % 0.0 [ -5.47, 5.47 ]
Subtotal (95% CI) 14 6 100.0 % 0.0 [ -5.47, 5.47 ]

2 SF-36 Mental
Bajaj 2008 14 -46 (3) 6 -42 (7) 100.0 % -4.00 [ -9.82, 1.82 ]
Subtotal (95% CI) 14 6 100.0 % -4.00 [ -9.82, 1.82 ]

3 Change in Total SIP Score
Bajaj 2014a 14 0.37 (7.01) 16 1.18 (6.7) 35.0 % -0.81 [ -5.74, 4.12 ]
Mittal 2009 34 -6.24 (3.4) 31 -1.05 (2.6) 65.0 % -5.19 [ -6.65, -3.73 ]
Subtotal (95% CI) 48 47 100.0 % -3.66 [ -7.75, 0.44 ]

4 Change in SIP Psychological Score
Bajaj 2014a 14 1.11 (9.54) 16 4.18 (8.62) 4.7 % -3.07 [ -9.61, 3.47 ]
Mittal 2009 34 -4.69 (3.5) 31 -1.13 (2.4) 95.3 % -3.56 [ -5.01, -2.11 ]
Subtotal (95% CI) 48 47 100.0 % -3.54 [ -4.95, -2.12 ]

5 Change in SIP Physical Score
Bajaj 2014a 14 0.02 (4.99) 16 1.13 (5.26) 14.9 % -1.11 [ -4.78, 2.56 ]
Mittal 2009 34 -3.21 (2.1) 31 0.05 (2) 85.1 % -3.26 [ -4.26, -2.26 ]
Subtotal (95% CI) 48 47 100.0 % -2.94 [ -4.44, -1.44 ]

-10 -5 0 5 10

Analysis 1.5. Comparison 1 Probiotic versus placebo or no intervention, Outcome 5 Plasma ammonia
concentration (final and change scores) (µmol/L).
Outcome: 5 Plasma ammonia concentration (final and change scores) ( mol/L)
Mean Mean
Study or subgroup Probiotic No intervention Difference Weight Difference
1 1 month
Sharma 2008 30 68.7 (28.4) 31 69.3 (33.3) 5.8 % -0.60 [ -16.11, 14.91 ]
Ziada 2013 26 52.47 (21.72) 25 74.54 (23.33) 7.4 % -22.07 [ -34.45, -9.69 ]
Malaguarnera 2010 63 66.2 (28.8) 62 71.45 (29.8) 8.7 % -5.25 [ -15.53, 5.03 ]
Zhao 2013 40 72.87 (15.84) 40 76.35 (10.23) 11.7 % -3.48 [ -9.32, 2.36 ]
Liu 2004 20 38.6 (3.9) 20 41.5 (5.2) 13.4 % -2.90 [ -5.75, -0.05 ]
Subtotal (95% CI) 179 178 47.0 % -5.55 [ -10.67, -0.42 ]

2 2 months
Pereg 2011 18 42.1 (26.9) 18 45.2 (23.6) 5.4 % -3.10 [ -19.63, 13.43 ]
Bajaj 2008 14 50 (26) 6 40 (3) 6.6 % 10.00 [ -3.83, 23.83 ]
Bajaj 2014a 14 29.3 (13.7) 16 43.4 (19.7) 7.6 % -14.10 [ -26.13, -2.07 ]
Malaguarnera 2010 63 55.9 (15.5) 62 65.25 (22.3) 11.1 % -9.35 [ -16.09, -2.61 ]
Subtotal (95% CI) 109 102 30.7 % -5.11 [ -14.56, 4.34 ]

3 3 months
Mittal 2009 37 -7.31 (7.9) 36 -0.52 (7.8) 13.1 % -6.79 [ -10.39, -3.19 ]
Subtotal (95% CI) 37 36 13.1 % -6.79 [ -10.39, -3.19 ]

4 6 months
Qiao 2010 32 43.75 (17.58) 32 74.83 (20.75) 9.2 % -31.08 [ -40.50, -21.66 ]
Subtotal (95% CI) 32 32 9.2 % -31.08 [ -40.50, -21.66 ]

Total (95% CI) 357 348 100.0 % -8.29 [ -13.17, -3.41 ]
Heterogeneity: Tau2 = 43.98; Chi2 = 47.57, df = 10 (P<0.00001); I2 =79%
-100 -50 0 50 100


Analysis 2.1. Comparison 2 Probiotic versus lactulose, Outcome 1 All-cause mortality.
Comparison: 2 Probiotic versus lactulose
Outcome: 1 All-cause mortality
Study or subgroup Probiotic Lactulose Risk Ratio Weight Risk Ratio

M- M-
n/N n/N CI CI
1 1 month
Zhao 2013 0/40 0/40 Not estimable

Total events: 0 (Probiotic), 0 (Lactulose)
2 2 months
Mouli 2014 2/60 0/60 100.0 % 5.00 [ 0.25, 102.00 ]
Subtotal (95% CI) 60 60 100.0 % 5.00 [ 0.25, 102.00 ]

Total (95% CI) 100 100 100.0 % 5.00 [ 0.25, 102.00 ]
Test for subgroup differences: Not applicable
0.005 0.1 1 10 200

Favours probiotic Favours lactulose

Analysis 2.2. Comparison 2 Probiotic versus lactulose, Outcome 2 No recovery (incomplete resolution of
clinical symptoms).
Outcome: 2 No recovery (incomplete resolution of clinical symptoms)

M- M-
n/N n/N CI CI
1 1 month or less
Loguercio 1995 3/18 8/19 2.4 % 0.40 [ 0.12, 1.26 ]
Loguercio 1987 6/16 9/15 5.6 % 0.63 [ 0.29, 1.33 ]
Ziada 2013 13/27 13/26 10.6 % 0.96 [ 0.56, 1.67 ]
Sharma 2008 15/31 14/31 11.3 % 1.07 [ 0.63, 1.82 ]
Zhao 2013 24/36 23/36 28.0 % 1.04 [ 0.74, 1.46 ]
Subtotal (95% CI) 128 127 57.8 % 0.94 [ 0.75, 1.20 ]

2 2 months
Mouli 2014 22/45 25/50 19.2 % 0.98 [ 0.65, 1.47 ]
Subtotal (95% CI) 45 50 19.2 % 0.98 [ 0.65, 1.47 ]

3 3 months
Mittal 2009 26/40 21/40 23.0 % 1.24 [ 0.85, 1.80 ]
Subtotal (95% CI) 40 40 23.0 % 1.24 [ 0.85, 1.80 ]

Total (95% CI) 213 217 100.0 % 1.01 [ 0.85, 1.21 ]
0.1 0.2 0.5 1 2 5 10


Analysis 2.3. Comparison 2 Probiotic versus lactulose, Outcome 3 Adverse events.
Outcome: 3 Adverse events

M- M-
n/N n/N CI CI
1 Overt hepatic encephalopathy
Zhao 2013 2/40 1/40 6.8 % 2.00 [ 0.19, 21.18 ]
Mittal 2009 2/40 1/40 6.8 % 2.00 [ 0.19, 21.18 ]
Ziada 2013 1/30 2/30 6.9 % 0.50 [ 0.05, 5.22 ]
Loguercio 1987 1/20 2/20 7.0 % 0.50 [ 0.05, 5.08 ]
Loguercio 1995 2/21 1/19 7.0 % 1.81 [ 0.18, 18.39 ]
Mouli 2014 12/60 10/60 65.5 % 1.20 [ 0.56, 2.56 ]
Subtotal (95% CI) 211 209 100.0 % 1.17 [ 0.63, 2.17 ]

2 Infection
3 Hospitalisation
Mittal 2009 1/40 3/40 100.0 % 0.33 [ 0.04, 3.07 ]
Subtotal (95% CI) 40 40 100.0 % 0.33 [ 0.04, 3.07 ]

4 Intolerance leading to discontinuation
Ziada 2013 0/30 2/30 22.4 % 0.20 [ 0.01, 4.00 ]
Loguercio 1987 1/20 2/20 37.4 % 0.50 [ 0.05, 5.08 ]
Mouli 2014 1/60 3/60 40.2 % 0.33 [ 0.04, 3.11 ]
Subtotal (95% CI) 110 110 100.0 % 0.35 [ 0.08, 1.43 ]

5 Change of/or withdrawal from treatment
0.01 0.1 1 10 100

(Continued . . . )

(. . .Continued)
M- M-
n/N n/N CI CI
Loguercio 1987 1/20 2/20 2.4 % 0.50 [ 0.05, 5.08 ]
Mittal 2009 3/40 1/40 2.7 % 3.00 [ 0.33, 27.63 ]
Loguercio 1995 6/21 1/19 3.2 % 5.43 [ 0.72, 41.09 ]
Sharma 2008 4/35 4/35 7.7 % 1.00 [ 0.27, 3.69 ]
Ziada 2013 4/30 6/30 9.7 % 0.67 [ 0.21, 2.13 ]
Zhao 2013 6/40 5/40 10.8 % 1.20 [ 0.40, 3.62 ]
Mouli 2014 27/60 20/60 63.5 % 1.35 [ 0.86, 2.13 ]
Subtotal (95% CI) 246 244 100.0 % 1.27 [ 0.88, 1.82 ]

0.01 0.1 1 10 100


Analysis 2.4. Comparison 2 Probiotic versus lactulose, Outcome 4 Health-related quality of life.
Outcome: 4 Health-related quality of life
Mean Mean
Study or subgroup Probiotic Lactulose Difference Weight Difference
1 Change in Total SIP Score

Mittal 2009 34 -6.24 (3.4) 35 -6.89 (4.1) 100.0 % 0.65 [ -1.13, 2.43 ]
Subtotal (95% CI) 34 35 100.0 % 0.65 [ -1.13, 2.43 ]

2 Change in SIP Psychological Score
Mittal 2009 34 -4.69 (3.5) 35 -5.17 (2.9) 100.0 % 0.48 [ -1.04, 2.00 ]
Subtotal (95% CI) 34 35 100.0 % 0.48 [ -1.04, 2.00 ]

3 Change in SIP Physical Score
Mittal 2009 34 -3.21 (2.1) 35 -3.59 (2.1) 100.0 % 0.38 [ -0.61, 1.37 ]
Subtotal (95% CI) 34 35 100.0 % 0.38 [ -0.61, 1.37 ]

-4 -2 0 2 4

Analysis 2.5. Comparison 2 Probiotic versus lactulose, Outcome 5 Plasma ammonia concentration (final
and change scores) (µmol/L).
Outcome: 5 Plasma ammonia concentration (final and change scores) ( mol/L)
Mean Mean
Study or subgroup Probiotic Lactulose Difference Weight Difference
1 1 month or less
Sharma 2008 31 75.7 (33) 31 69.3 (33.3) 9.9 % 6.40 [ -10.10, 22.90 ]
Loguercio 1995 14 57.3 (19.8) 11 62.7 (17.3) 11.6 % -5.40 [ -19.96, 9.16 ]
Ziada 2013 26 52.47 (21.72) 24 55.64 (28.1) 12.2 % -3.17 [ -17.17, 10.83 ]
Loguercio 1987 16 58.72 (5.87) 15 76.33 (17.62) 17.9 % -17.61 [ -26.98, -8.24 ]
Zhao 2013 40 72.87 (15.84) 40 71.56 (16.17) 21.4 % 1.31 [ -5.70, 8.32 ]
Subtotal (95% CI) 127 121 73.0 % -4.30 [ -13.17, 4.56 ]

2 3 months
Mittal 2009 37 -7.31 (7.9) 40 -8.47 (5.8) 27.0 % 1.16 [ -1.96, 4.28 ]
Subtotal (95% CI) 37 40 27.0 % 1.16 [ -1.96, 4.28 ]

Total (95% CI) 164 161 100.0 % -2.93 [ -9.36, 3.50 ]
-50 -25 0 25 50
ADDITIONAL TABLES
Table 1. Types of probiotics used across studies
Study Probiotics used
Bajaj 2008 Streptococcus thermophilus,Lactobacillus bulgaricus,Lactobacillus acidophilus,Lactobacillus casei,Bifidobacteria
Bajaj 2014a Lactobacillus GG AT strain 53103

Table 1. Types of probiotics used across studies (Continued)
Dhiman 2013a VSL#3 (containing Bifidobacterium breve,Bifidobacterium longum,Bifidobacterium infantis,Lactobacillus aci-

dophilus,Lactobacillus plantarum,Lactobacillus paracasei,Lactobacillus bulgaricus, Streptococcus thermophilus)
Liu 2004 Pediacoccus pentosaceus,Leuconostoc mesenteroides,Lactobacillus paracasei,Lactobacillus plantarum
Loguercio 1987 Enterococcus lactic acid bacteria strain SF68
Loguercio 1995 Enterococcus faecium strain SF68
Lunia 2014 VSL#3 (containing Streptococcus thermophilus,Bifidobacterium breve,Bifidobacterium longum,Bifidobacterium

infantis,Lactobacillus acidophilus,Lactobacillus plantarum,Lactobacillus paracasei,Lactobacillus bulgaricus)
Malaguarnera 2010 Bifidobacterium (subtype not available)
Mittal 2009 VSL#3 (containing Streptococcus thermophilus,Bifidobacterium breve,Bifidobacterium longum,Bifidobacterium

infantis,Lactobacillus acidophilus,Lactobacillus plantarum,Lactobacillus paracasei,Lactobacillus bulgaricus)
Mouli 2014 VSL#3 (4 strains of Lactobacillus (L acidophilus DSM 24735, L plantarum DSM 24730, L paracasei DSM
24733, L delbrueckii subsp. bulgaricus DSM 24734), 3 strains of Bifidobacterium (B longum DSM 24736,
B breve DSM 24732, B infantis DSM 24737), and 1 strain of Streptococcus (S thermophilus DSM 24731))
Nair 2008 Lactobacillus acidophilus,Lactobacillus rhamnosus,Bifidobacterium longum,Saccharomyces boulardii
Pereg 2011 Lactobacillus acidophilus, Lactobacillus bulgaricus, Bifidobacterium bifidum, Streptococcus thermophilus (Bio
Plus, Supherb, Israel)
Qiao 2010 Bifid triple viable (not further specified)
Saji 2011 Lactobacillus acidophilus,Lactobacillus rhamnosus,Bifidobacterium longum,Saccharomyces boulardii
Sharma 2008 Enterococcus faecalis,Clostridium butyricum,Bacillus mesentricus, lactic acid Bacillus
Sharma 2014 Velgut ERIS Pharmaceuticals, Ahmadabad, India (Lactobacillus acidophilus,Lactobacillus rhamnosus,Lacto-
bacillus plantarum,Lactobacillus casei,Bifidobacterium longum,Bifidobacterium infantis,Bifidobacterium breve,
Saccharomyces boulardii,Streptococcus thermophilus)
Shavakhi 2014 Balance (Protexin Co., Somerset, UK) Lactobacillus strains (L casei,L rhamnosus,L acidophilus,L bulgaricus)
,Bifidobacterium strains (B breve, B longum), andStreptococcus thermophilus
Vlachogiannakos 2014 Lactobacillus plantarum 299v
Zhao 2013 Unclear
Zhitai 2013 Live Bacillus cereus capsules
Ziada 2013 Lactobacillus acidophilus

Table 2. Heterogeneity subgroup analysis
Probiotic versus placebo or no intervention Probiotic versus
No-recovery Studies Participants Effect estimate Difference P

Risk ratio [95% CI]
Type of probiotic 10 574 - 0.69
Lactobacillus 4 195 0.67 [0.45, 1.00] -
Mixed 5 309 0.65 [0.50, 0.83] -
Unclear 1 70 0.76 [0.58, 0.98] -
Grade of hepatic en- 10 574 - 0.06

cephalopathy
Minimal 8 473 0.63 [0.52, 0.76] -
Overt 2 101 0.98 [0.64, 1.48] -
Duration of therapy 10 574 - 0.43
<= 1 month 4 228 0.75 [0.58, 0.96] -
1 > 2 months 3 117 0.65 [0.38, 1.10] -
2 + months 3 229 0.58 [0.43, 0.78] -
Co-interventions 10 574 - 0.17
No treatment 8 473 0.63 [0.52, 0.76] -
Bioactive fermentable fi- 1 40 1.00 [0.54, 1.86] -

bre
Lactulose 1 61 0.96 [0.55, 1.69] -
Plasma ammonia con- Studies Participants Effect estimate Difference P

centration Mean difference [95% CI]
Bifidobacterium 1 125 -9.35 [-16.09, -2.61] -
Lactobacillus 3 121 -11.90 [-24.41, 0.60] -
Mixed 4 190 -1.80 [-9.65, 6.06] -
Unclear 2 144 -17.02 [-44.07, 10.02] -

Table 2. Heterogeneity subgroup analysis (Continued)

cephalopathy
Minimal 9 455 -8.50 [-14.38, -2.62] -
Overt 1 125 -9.35 [-16.09, -2.61] -
Duration of therapy 10 580 - 0.58
<=1 month 4 232 -5.93 [-12.25, 0.39] -
1 > 2 months 4 211 -5.11 [-14.56, 4.34] -
2 + months 2 137 -18.53 [-42.32, 5.26] -
Co-interventions used 10 580 - 0.11
No treatment 7 354 -10.42 [-18.68, -2.17] -
Bioactive fermentable fi- 1 40 -2.90 [-5.51, -0.29] -

bre
Lactulose 2 186 -7.88 [-14.29, -1.47] -
Probiotic versus lactulose Probiotic versus
Plasma ammonia con- Studies Participants Effect estimate Difference P

centration Mean difference [95% CI]
Enterococcus SF68 2 56 -12.83 [-24.51, -1.15] -
Mixed 2 139 1.34 [-1.72, 4.40] -
Lactobacillus 1 50 -3.17 [-17.17, 10.83] -
Unclear 1 80 1.31 [-5.70, 8.32] -

cephalopathy
Minimal 4 269 1.16 [-1.59, 3.91] -
Overt 2 56 -12.83 [-24.51, -1.15] -

CI: confidence interval

APPENDICES
Appendix 1. Search strategies
Database Span of search Search strategy
The Cochrane Hepato-Biliary Group Con- August 2015 (probiot* OR lactobacil* OR bifidobacter*) AND (’hepatic en-
trolled Trials Register cephalopath*’ OR (liver AND (diseas* OR cirrhosis*)))
Cochrane Central Register of Controlled 2016, Issue 5. #1 LIVER CIRRHOSIS explode all trees (MeSH)
Trials (CENTRAL) in the Cochrane Li- #2 (liver cirrhosis):ti,ab,kw
brary #3 HEPATIC ENCEPHALOPATHY explode all trees (MeSH)
#4 (hepatic encephalopathy):ti,ab,kw
#5 (liver next cirrhosis)
#6 (hepatic next encephalopathy)
#7 (#1 or #2 or #3 or #4 or #5 or #6)
#8 probiotics explode all trees (MeSH)
#9 (probiotics):ti,ab,kw
#10 lactobacillus explode all trees (MeSH)
#11 (lactobacillus):ti,kw,ab
#12 bifidobacterium explode all trees (MeSH)
#13 (bifidobacterium):ti,kw,ab
#14 (#8 or #9 or #10 or #11 or #12 or #13)
#15 (#7 and #14)
MEDLINE Ovid 1946 to June 2016. #1 randomised controlled trial.pt. [#1 randomized controlled
trial.pt. in 2015 update]
#2 controlled clinical trial.pt.
#3 randomized.ab.
#4 placebo.ab.
#5 drug therapy.fs.
#6 randomly.ab.
#7 trial.ab.
#8 groups.ab.
#9 or/1-8
#10 animals.sh.
#11 9 not 10
#12 exp hepatic encephalopathy/
#13 hepatic encephalopathy.tw
#14 exp liver cirrhosis/
#15 liver cirrhosis.tw
#16 12 or 13 or 14 or 15
#17 exp probiotics/
#18 probiotic.tw
#19 exp lactobacillus/
#20 lactobacillus.tw
#21 exp bifidobacterium/
#22 bifidobacterium.tw
#23 17 or 18 or 19 or 20 or 21 or 22
#24 11 and 16 and 23

(Continued)
Embase Ovid 1974 to June 2016. #1 random:.tw.

#2 clinical trial:.mp.
#3 exp health care quality/
#4 1 or 2 or 3
#5 exp hepatic encephalopathy/
#6 hepatic encephalopathy.tw
#7 exp liver cirrhosis/
#8 liver cirrhosis.tw
#9 5 or 6 or 7 or 8
#10 exp probiotics/
#11 probiotic.tw
#12 exp lactobacillus/
#13 lactobacillus.tw
#14 exp bifidobacterium/
#15 bifidobacterium.tw
#16 10 or 11 or 12 or 13 or 14 or 15
#17 4 and 9 and 16
Science Citation Index Expanded (Web of 1900 to June 2016. # 1 TS=(probiotic OR probiot* OR lactobacil* OR bifidobacter*)
Science) # 2 TS=(hepatic encephalopath* OR liver diseas*)
# 3 #1 AND #2
# 4 TS=(random* OR blind* OR placebo*)
# 5 #3 AND #4
WHAT’S NEW
Last assessed as up-to-date: 14 June 2016.
Date Event Description
14 June 2016 New citation required and conclusions have changed The conclusions changed from “While probiotics appear
to reduce plasma ammonia concentration when compared
with placebo or no intervention, we are unable to conclude
that probiotics are efficacious in altering clinically relevant
outcomes” (McGee 2011), to “Overall, probiotics appear to
help symptom resolution, reduce plasma ammonia concen-
trations, and result in less overt hepatic encephalopathy com-
pared with no treatment, although we consider the evidence
to be of low quality”
14 June 2016 New search has been performed June 2016 search update: Seven new trials added. The review
is now based on 21 trials with a total of 1420 participants

CONTRIBUTIONS OF AUTHORS
RD: participated in all stages of the review.
RMG: conceived the review, designed the protocol, and participated in all stages of the review.
SMR: drafted the protocol, contributed to the search, provided content area advice, and reviewed the manuscript.
ACW: drafted the protocol, provided methodological advice, contributed to study design, and reviewed the manuscript.
DECLARATIONS OF INTEREST
RD: is a recipient of a scholarship from The University of Sydney. This scholarship had no influence on the conduct of this review.
RMG: none to declare.
SMR: is an author of a trial included in the review. SMR had no influence on its inclusion or data extraction and analysis.
ACW: none to declare.
SOURCES OF SUPPORT
Internal sources
• No financial support was received for the conduct of this review, Australia.
External sources
• No financial support was received for the conduct of this review, Australia.
DIFFERENCES BETWEEN PROTOCOL AND REVIEW

The following changes have been made in the update.
• The search terms used have been updated to keep the search strategy up to date.
• The outcome adverse events, which previously reported “number of adverse events”, has been expanded to include overt hepatic
encephalopathy, infections, hospitalisations, intolerance leading to discontinuation, and change of/or withdrawal from treatment.
• The previous outcome “change of/or withdrawal from treatment” is now a subgroup of adverse events.
• Final and change scores have been combined into the same analysis for plasma ammonia concentration.

INDEX TERMS
Medical Subject Headings (MeSH)

Gastrointestinal Agents [∗ therapeutic use]; Hepatic Encephalopathy [mortality; ∗ therapy]; Lactulose [∗ therapeutic use]; Probiotics
[∗ therapeutic use]; Quality of Life; Randomized Controlled Trials as Topic
MeSH check words

Humans


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Cochrane Database of Systematic Reviews

Probiotics for people with hepatic encephalopathy (Review)

Dalal R, McGee RG, Riordan SM, Webster AC

Dalal R, McGee RG, Riordan SM, Webster AC.

Probiotics for people with hepatic encephalopathy (Review)

Probiotics for people with hepatic encephalopathy (Review) i

Probiotics for people with hepatic encephalopathy

Rohan Dalal1 , Richard G McGee2 , Stephen M Riordan3 , Angela C Webster4

Editorial group: Cochrane Hepato-Biliary Group.

Data collection and analysis

PLAIN LANGUAGE SUMMARY

Probiotics for people with hepatic encephalopathy (Review) 3

Probiotic versus placebo or no intervention for people with hepatic encephalopathy

Patient or population: people with hepatic encephalopathy

Risk with placebo/ no Risk with probiotic

All-cause m ortality Study population RR 0.58 404 ⊕⊕

25 per 1000 14 per 1000

No-recovery (incom - Study population RR 0.67 574 ⊕⊕⊕

877 per 1000 588 per 1000

Adverse events - Overt Study population RR 0.29 585 ⊕⊕

169 per 1000 49 per 1000

Adverse Study population RR 0.70 551 ⊕

158 per 1000 111 per 1000

Quality of lif e - - - 115 ⊕⊕

Plasm a am m onia con- - The m ean plasm a - 705 ⊕⊕

GRADE Working Group grades of evidence

(m ost studies at high risk of bias).

How the intervention might work METHODS

Probiotics for people with hepatic encephalopathy (Review) 7

Probiotics for people with hepatic encephalopathy (Review) 8

Searching other resources Assessment of risk of bias in included studies

Probiotics for people with hepatic encephalopathy (Review) 9

Selective outcome reporting Assessment of heterogeneity

Probiotics for people with hepatic encephalopathy (Review) 10

Probiotics for people with hepatic encephalopathy (Review) 11

Probiotics for people with hepatic encephalopathy (Review) 12

Probiotics for people with hepatic encephalopathy (Review) 13

Probiotics for people with hepatic encephalopathy (Review) 14

Probiotics for people with hepatic encephalopathy (Review) 15

Probiotics for people with hepatic encephalopathy (Review) 16

Probiotics for people with hepatic encephalopathy (Review) 17

Probiotics for people with hepatic encephalopathy (Review) 18

Probiotic versus lactulose for people with hepatic encephalopathy

Patient or population: people with hepatic encephalopathy

Risk with lactulose Risk with probiotic

All-cause m ortality Study population RR 5.00 200 ⊕

No-recovery (incom - Study population RR 1.01 430 ⊕

500 per 1000 505 per 1000

Adverse events - Overt Study population RR 1.17 420 ⊕

60 per 1000 70 per 1000

Adverse Study population RR 1.27 490 ⊕

114 per 1000 145 per 1000

Quality of lif e It is uncertain whether probiotics im prove quality - 69 ⊕

Plasm a am m onia con- - The m ean plasm a - 325 ⊕

GRADE Working Group grades of evidence

(m ajority of studies at high risk of bias).

Overall completeness and applicability of

Probiotics for people with hepatic encephalopathy (Review) 22

Probiotics for people with hepatic encephalopathy (Review) 23